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ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Assessment of
iodine deficiency disorders and
monitoring their elimination
This document is intended primarily for managers of national program-
mes for the prevention and control of micronutrient malnutrition.
It sets out principles governing the use of surveillance indicators in imple-
menting interventions to prevent, control, and monitor iodine deficiency
disorders (IDD). It presents methods for monitoring iodine status and
determining urinary iodine and provides guidelines on the procedures for
monitoring salt iodine content, whether at the factory, importation site, or
household level. It also gives guidance on conducting surveys to assess
iodine status in populations.
Finally, indicators are presented for monitoring progress towards achie-
ving the goal of sustainable elimination of IDD as a significant public
health problem.

A GUIDE FOR PROGRAMME MANAGERS


Third edition

ISBN 978 92 4 159582 7


WHO
Assessment of
iodine deficiency disorders
and monitoring their
elimination
A GUIDE FOR PROGRAMME MANAGERS
Third edition
WHO Library Cataloguing-in-Publication Data
Assessment of iodine deficiency disorders and monitoring their
elimination : a guide for programme managers. – 3rd ed.
1.Iodine – deficiency. 2.Nutrition disorders – prevention and
control. 3.Sodium chloride, Dietary – therapeutic use. 4.Nutrition
assessment. 5.Nutrition policy – standards. 6.Guidelines. I.World
Health Organization.
ISBN 978 92 4 159582 7 (NLM classification: WK 250)

This report contains the collective views of an international group of


experts, and does not necessarily represent the decisions or the stated
policy of the World Health Organization.

© World Health Organization 2007


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Contents

Abbreviations vi
Preface vii
1 Introduction 1
1.1 About this manual 1
1.2 Defi nitions 3
1.3 Monitoring and evaluating IDD control programmes 3
1.4 Indicators described in this manual 4
2 IDD and their control, and global progress in their elimination 6
2.1 The iodine deficiency disorders 6
2.2 Correction of iodine deficiency 8
2.3 Universal salt iodization (USI) 10
2.4 Iodine supplementation 12
2.5 Sustainability 12
2.6 Global progress in the elimination of IDD 14
2.7 Challenges for the future: consolidating the achievement 14
3 Indicators of the salt iodization process 17
3.1 Factors that determine salt iodine content 17
3.2 Determining salt iodine levels 20
3.3 Indicators for monitoring at different levels 22
4 Indicators of impact 28
4.1 Overview 28
4.2 Urinary iodine 28
4.3 Thyroid size 34
4.4 Blood constituents 38
5 Monitoring and evaluation methods 44
5.1 Overview 44
5.2 Monitoring and evaluation of salt iodization programs 44
5.3 Iodine status assessment 47
5.4 Thyroid function assessment 48
5.5 Common monitoring methods 48
5.6 Combined micronutrient deficiency surveys 51

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ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

6 Indicators of the sustainable elimination of IDD 52


6.1 With regard to salt iodization 52
6.2 With regard to the population’s iodine status 52
6.3 With regard to the programmes 53
6.4 Programme evaluation 54
Annexes 55
Annex 1 Titration method for determining salt iodate and
salt iodide content 57
Annex 2 Method for determining thyroid size by ultrasonography 62
Annex 3 Method for measuring urinary iodine using
ammonium persulfate (method A) 66
Annex 4 Methodology for selection of survey sites by PPS
sampling 70
Annex 5 Summarizing urinary iodine data: a worked example 78
Annex 6 Guidelines to assess IDD national programmes 83
Annex 7 List of Contributors 91
References 95
List of tables
Table 1 The spectrum of iodine deficiency disorders (IDD) 7
Table 2 Recommended dosages of daily and annual iodine
supplementation 12
Table 3 Proportion of population and number of individuals
in the general population (all age groups) with
insufficient iodine intake by WHO regions during
the period between 1994 and 2006, and proportion of
households using iodized salt 15
Table 4 Epidemiological criteria for assessing iodine nutrition
based on median urinary iodine concentrations of
school-age children (≥6 years) 33
Table 5 Epidemiological criteria for assessing iodine nutrition
based on the median or range in urinary iodine
concentrations of pregnant women 33
Table 6 Simplified classification of goitre by palpation 36
Table 7 Epidemiological criteria for assessing the severity of
IDD based on the prevalence of goitre in school-age
children 37
Table 8 Gender-specific 97th percentile (P97) of thyroid
volume (ml) by age and body surface area (BSA)
measured by ultrasound in iodine-sufficient
6-12 yr-old children 38

iv
CONTENTS

Table 9 Indicators of impact at population level: summary 43


Table 10 Summary of criteria for monitoring progress towards
sustainable elimination of IDD as a public health
problem 54
Table 11 Selection of communities in El Saba using the PPS
method 72
Table 12 Selection of schools using the PPS method 74
Table 13 Selection of schools using the systematic selection
method 76
Table 14 Summary of results 79
Table 15 Urinary iodine data in Cameroon schoolchildren
following salt iodization 80
Table 16 Summary of salt situation 87
Table 17 Summary of Country Program assessments 89

List of figures
Figure 1 National IDD control programming cycle 9
Figure 2 A monitoring and evaluation system for salt iodization 23
Figure 3 Anatomic description of the thyroid gland 62
Figure 4 Transverse scan 64
Figure 5 Longitudinal scan 64
Figure 6 Frequency table and histogram to show distribution of
urinary iodine values after iodization in Cameroon 82
Figure 7 Flow chart for Network Country Review 85

v
Abbreviations

BSA Body surface area


HDPE High-density polyethylene
HIV Human immunodeficiency virus
ICCIDD International Council for Control of IDD
IDD Iodine deficiency disorders
IIH Iodine-induced hyperthyroidism
IQ Intelligence quotient
ISO International Organization for Standardization
LDPE Low-density polyethylene
LQAS Lot quality assurance sampling
MICS Multiple indicator cluster survey
N Number
P Percentile
PAMM Programme Against Micronutrient Malnutrition
ppm Parts per million
PPS Proportionate to population size
RTK Rapid test kits
SD Standard deviation
SOWC State of the world’s children
T3 Triiodothyronine
T4 Thyroxin
Tg Thyroglobulin
TGR Total goitre rate
TSH Thyroid stimulating hormone
UI Urinary iodine
UN United Nations
UNICEF United Nations Children’s Fund
US United States of America
USI Universal salt iodization
WHO World Health Organization
µg Micrograms (millionths of a gram)

vi
Preface

Knowledge obtained over the last decade through research and practical
use of the Assessment of Iodine Deficiency Disorders and Monitoring their
Elimination guidelines, edited by WHO in collaboration with UNICEF
and ICCIDD, has validated new indicators with public health signifi-
cance. This progression has necessitated this new, third edition of these
guidelines.
New indicators of thyroid function have been included, such as meas-
urement of thyroid volume by ultrasound, as there are new international
reference standards, and the measurement of serum thyroglobulin for
which thresholds have been validated to differentiate normal status from
deficiency. In addition, new iodine requirements for pregnant and lac-
tating women have been provided, which results in an increased median
urinary iodine concentration to defi ne a public health problem in preg-
nant women. Lastly, the programmatic criteria to assess progress towards
the elimination of iodine deficiency were revised in light of experience
accumulated in the field.
As a fi rst step to revise the guidelines, experts on iodine were com-
missioned to review and update various sections of the previous version
of the document published in 2000. The ensuing updated sections were
then used as the background document for an expert technical consul-
tation held in Geneva, Switzerland from 22–23 January 2007, with the
objective of conducting a critical analysis of the revised sections, and of
subsequently developing a new document. This revised version was then
distributed widely; not only to participants in the consultation, but also
to other experts in IDD prevention and control whose helpful comments
and suggestions are reflected herein.
Salt iodization is currently the most widely used strategy to control
and eliminate IDD. However, to be fully effective in correcting iodine
deficiency, salt must not only reach the entire affected population (in
particular those groups that are the most susceptible, pregnant women
and young children) but it also needs to be adequately iodized. This is
why these guidelines emphasize process indicators; in particular, those
related to the monitoring of iodized salt at the production and/or impor-

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ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

tation levels, and iodized salt use in the population. Such monitoring
necessarily involves both governments and the salt industry, requiring
close collaboration between the public and private sectors.
Impact indicators are meant to assess the magnitude of IDD as a
public health problem and to monitor the effects of the intervention on
the iodine status of a population. This manual recommends the use of
urinary iodine to monitor impact. Blood TSH and thyroglobulin may
also be useful for assessing impact, but their use is still limited due to
their cost. The measurement of thyroid size by palpation or ultrasound
was useful initially, but is less useful once salt iodization is established.
For each impact indicator, this manual provides information on biological
features, methods of measurement, and criteria for selecting those
methods and the interpretation of results. The statistical methodology
employed to carry out a survey is also described.
IDD elimination is achieved only if salt iodization can be sustained.
The fi nal chapter addresses this issue, and provides criteria to determine
whether a programme of IDD control is sustainable.
This document is intended primarily for managers of national
programmes dealing with the prevention and control of micronutrient
malnutrition, as well as for policy makers. We hope that the information
included in this manual will be useful, and that it will contribute to our
common goal of the elimination of IDD.

Bruno de Benoist
Coordinator
Micronutrient Malnutrition Unit
Department of Nutrition for Health Development
World Health Organization

Gerald Burrow
Chairman
International Council for Control of Iodine Deficiency Disorders

Werner Schultink
Chief, Nutrition Section
United Nations Children’s Fund

viii
1 Introduction

1.1 About this manual


The importance of iodine deficiency disorders (IDD)
Iodine deficiency, through its effects on the developing brain, has con-
demned millions of people to a life of few prospects and continued
underdevelopment. On a worldwide basis, iodine deficiency is the single
most important preventable cause of brain damage.
People living in areas affected by severe iodine deficiency may have an
intelligence quotient (IQ) of up to 13.5 points below that of those from
comparable communities in areas where there is no iodine deficiency
(1). This mental deficiency has an immediate effect on child learning
capacity, women’s health, the quality of life in communities, and eco-
nomic productivity.
On the other hand, IDD are among the easiest and least expensive of all
nutrient disorders to prevent. The addition of a small, constant amount
of iodine to the salt that people consume daily is all that is needed. The
elimination of IDD is a critical development issue, and should be given
the highest priority by governments and international agencies.
Recognizing the importance of preventing IDD, the World Health
Assembly adopted in 1991 the goal of eliminating iodine deficiency as
a public health problem. In 1990, world leaders had endorsed this goal
when they met at the World Summit for Children at the United Nations.
It was reaffi rmed by the International Conference on Nutrition in 1992.
In 1993, WHO and UNICEF recommended universal salt iodization
(USI)1 as the main strategy to achieve elimination of IDD (2). In 2005,
the importance of IDD elimination was again recognized when the
World Health Assembly adopted a resolution committing to reporting
on the global IDD situation every three years.
Since 1990, there has been tremendous progress in increasing the
proportion of dietary salt which is adequately iodized. As a result, many
countries have achieved, or are now on the threshold of achieving IDD

1
Universal salt iodization (USI) is defi ned as when all salt for human and animal con-
sumption is iodized to the internationally agreed recommended levels.

1
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

elimination. In those countries, the emphasis will shift to ensuring that


these achievements are permanently sustained.

Objectives of this manual


Progress towards the elimination of IDD can only be demonstrated if it
is measured. This requires the selection of appropriate indicators of both
process and impact.
Sound techniques are needed in order to reliably measure indicators
of IDD, and these techniques must be applied using suitable epidemio-
logical methods that take target population, geographical area, and tim-
ing of survey factors into account.
Finally, the results should be presented in a format that is easily inter-
preted and comparable to those from other regions or countries.
Specifically, the objectives of this manual are to describe:
• The indicators used in assessing the magnitude of IDD at different
stages of the USI programme, and in monitoring and evaluating
salt iodization and any other interventions for the control of IDD
and their impact;
• How to use and apply these indicators in practice;
• How to assess whether iodine deficiency has been successfully
eliminated;
• How to judge whether achievements can be sustained and main-
tained for the decades to come.

Target audience
This book is aimed primarily at IDD programme managers and others
in government who are involved in the implementation of IDD control
programmes. It is also aimed at the salt industry and all others involved
in IDD elimination.

Origins of this book


This is the second revised version of the original document, which was
entitled “Indicators for assessing Iodine Deficiency Disorders and their
control through salt iodization” (3). That document was produced fol-
lowing a consultation held in Geneva in November 1992.
After a considerable amount of new information on the identifica-
tion, prevention and control of IDD had been generated, and the public
health focus regarding this significant problem had shifted to empha-
size the importance of the process indicators, a second revision of this
book was published in 2001 based on a Consultation held in Geneva in
1999. It involved experts on IDD from all three partner organizations,

2
1. INTRODUCTION

WHO, UNICEF, and ICCIDD, representing all regions of the world


(see Annex 7).
In 2007, experts and the three partner organizations gathered again
for a consultation in Geneva to update the manual to include new knowl-
edge, including new iodine requirements in pregnant and lactating
women, refi nements in monitoring household iodized salt use, and infor-
mation on measuring thyroglobulin as an impact indicator.

1.2 Definitions
Iodine deficiency disorders (IDD) refer to all of the consequences of
iodine deficiency in a population that can be prevented by ensuring that
the population has an adequate intake of iodine. For further details, see
Chapter 2.
Indicators are used to help describe a situation that exists, and can
be used to track changes in the situation over time. Indicators are usu-
ally quantitative (i.e. measurable in some way), but they may also be
qualitative.
Monitoring is the process of intermittently collecting and analysing
information about a programme for the purpose of identifying prob-
lems, such as non-compliance, and taking corrective action so as to meet
stated objectives.
Evaluation is a process that attempts to determine as systematically
and objectively as possible the relevance, effectiveness, and impact of
activities relevant to their objectives (4).

1.3 Monitoring and evaluating IDD control programmes


Monitoring of any health intervention is essential to ensure that it is func-
tioning as planned and to provide information needed to take corrective
action if necessary. In addition, periodic evaluation of health programmes
is necessary to ensure that overall goals and objectives are being met.
Salt iodization programmes, like any other health interventions,
therefore require an effective system for monitoring and evaluation. The
challenge is to apply the IDD indicators using valid and reliable methods
while keeping costs to a minimum. To this end, it is essential to clearly
formulate questions to which answers are needed, since the methods
used to gather data may be very different. Important questions that will
need to be answered include:
• Is all the salt that is being produced or imported iodized to the
country’s requirements?
• Is adequately iodized salt reaching and being used by the popula-
tion in countries at risk of iodine deficiency?

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ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

• Are there any groups in the population that are not reached by
iodized salt, and thus require attention?
• What is the relative contribution to iodine intake from table salt
versus iodized salt used in the food industry?
• What impact are salt iodization and other interventions having on
the iodine status of the population?
In some countries there is still inadequate information on IDD, and pro-
grammes have not yet been implemented. Here the questions may be:
• Have IDD been eliminated as a public health problem?
• What is the prevalence of IDD in specific population groups (preg-
nant women, infants) based on geographical, administrative, or
physiological criteria?
• What steps are necessary to address IDD, such as a salt situation
analysis?
Answering these questions requires different approaches to gathering
data. It is therefore very important to be quite clear about the purpose of
a particular survey. See Annex 6 for guidelines to assess IDD national
programmes.

1.4 Indicators described in this manual


This manual describes the various indicators which are used in monitor-
ing and evaluating IDD control programmes. The indicators are divided
into three main groups:
1. Process indicators: indicators to monitor and evaluate the salt iodi-
zation process.
These indicators reflect monitoring salt iodine content at the produc-
tion/importation site and at the household level, and in some instanc-
es, checking at the retail/wholesale level. Consideration should also be
given to assessing the use of iodized salt in the food industry.

2. Impact indicators: indicators to assess iodine status and to monitor


and evaluate the impact of salt iodization on the population.
Median urinary iodine is the main indicator to be used to assess
iodine status of a population. Goitre assessment by palpation or by
ultrasound may be useful in assessing thyroid function, but is difficult
to interpret once salt iodization has started. The measurement of thy-
roid stimulating hormone (TSH) levels in neonates where a screening

4
1. INTRODUCTION

programme is in place, and of thyroglobulin in school-age children


where feasible are both useful indicators of thyroid function.
Once a salt iodization programme has been initiated, the principal
impact indicator recommended is the population median urinary
iodine level. Changes in goitre prevalence lag behind changes in
iodine status, and therefore cannot be relied upon to accurately reflect
current iodine intake.

3. Sustainability indicators: indicators to assess whether iodine defi-


ciency has been successfully eliminated and to judge whether achieve-
ments can be sustained and maintained for the decades to come.
This involves a combination of median urinary iodine levels in the
population, availability of adequately iodized salt at the household
level, and a set of programmatic indicators which are regarded as evi-
dence of sustainability (see Chapter 6).

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ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

2 IDD and their control,


and global progress in
their elimination

2.1 The iodine deficiency disorders


Recommended iodine intake
UNICEF, ICCIDD (5), and WHO (6) recommend that the daily intake
of iodine should be as follows:
• 90 µg for preschool children (0 to 59 months);
• 120 µg for schoolchildren (6 to 12 years);
• 150 µg for adolescents (above 12 years) and adults;
• 250 µg for pregnant and lactating women.

The iodine deficiency disorders


Iodine deficiency occurs when iodine intake falls below recommended
levels. It is a natural ecological phenomenon that occurs in many parts
of the world. The erosion of soils in riverine areas due to loss of vegeta-
tion from clearing for agricultural production, overgrazing by livestock,
and tree-cutting for fi rewood results in a continued and increasing loss
of iodine from the soil. Groundwater and foods grown locally in these
areas lack iodine.
When iodine intake falls below recommended levels, the thyroid may
no longer be able to synthesize sufficient amounts of thyroid hormone.
The resulting low level of thyroid hormones in the blood (hypothy-
roidism) is the principal factor responsible for damage to the developing
brain and other harmful effects known collectively as “iodine deficiency
disorders” (7). The adoption of this term emphasizes that the problem
extends far beyond simply goitre and cretinism (Table 1).
The most critical period is from the second trimester of pregnancy
to the third year after birth (8,9). Normal levels of thyroid hormones
are required for optimal development of the brain. In areas of iodine
deficiency, where thyroid hormone levels are low, brain development is
impaired. In its most extreme form, this results in cretinism, but of much
greater public health importance are the more subtle degrees of brain
damage and reduced cognitive capacity which affects the entire popula-
tion. As a result, the mental ability of ostensibly normal children and

6
2. IDD AND THEIR CONTROL, AND GLOBAL PROGRESS IN THEIR ELIMINATION

Table 1 The spectrum of iodine deficiency disorders (IDD) a


PHYSIOLOGICAL GROUPS HEALTH CONSEQUENCES OF IODINE DEFICIENCY

All ages Goitre


Hypothyroidism
Increased susceptibility to nuclear radiation
Fetus Spontaneous abortion
Stillbirth
Congenital anomalies
Perinatal mortality
Neonate Endemic cretinism including mental deficiency with a mixture of mutism,
spastic diplegia, squint, hypothyroidism and short stature
Infant mortality
Child and adolescent Impaired mental function
Delayed physical development
Iodine-induced hyperthyroidism (IIH)
Adults Impaired mental function
Iodine-induced hyperthyroidism (IIH)
a
Adapted from BS Hetzel, 1983 (7).

adults living in areas of iodine deficiency is reduced compared to what it


would be otherwise.
Thus, the potential of a whole community is reduced by iodine defi-
ciency. Where the deficiency is severe, there is little chance of achievement
and underdevelopment is perpetuated. Indeed, in an iodine-deficient
population, everybody may seem to be slow and rather sleepy. The qual-
ity of life is poor, ambition is blunted, and the community becomes
trapped in a self-perpetuating cycle. Even the domestic animals, such
as village dogs, are affected. Livestock productivity is also dramatically
reduced (10).

Identification of the occurrence of IDD


In the past, the likely occurrence of iodine deficiency in a given region
was regarded as being signalled by certain geographical characteristics.
These include mountain ranges and alluvial plains, particularly at high
altitude and at considerable distance from the sea. This occurrence was
confi rmed by a high prevalence of goitre in the resident population.
However, the greater use of urinary iodine estimation and other meth-
ods for assessing iodine deficiency (see Chapter 4) has demonstrated
that IDD can and does occur in many areas where none of these condi-
tions are met. Indeed, significant iodine deficiency has been found:
• Where the prevalence of goitre is low and doesn’t suggest a prob-
lem;

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ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

• In coastal areas;
• In large cities;
• In highly developed countries;
• Where iodine deficiency has been considered to have been elimi-
nated.
In recognition of a much wider occurrence of IDD than previously
thought, certain countries have come to regard the whole country as
being at risk of iodine deficiency and therefore the entire population as
a target for IDD control with iodized salt. The need for continued vigi-
lance is underlined, as is the importance of all countries carrying out
periodic urinary iodine surveys.

2.2 Correction of iodine deficiency


Administrative arrangements
The national body responsible for the management of the IDD control
programme should operate with a process model. A useful example of
such a process model is known as the “wheel” (Figure 1).
This cycle, which is described in details following, shows the differ-
ent elements of national IDD control. The successful achievement of
this overall process requires the establishment of a national IDD con-
trol commission, with the ability to influence the political and legislative
process. Several elements included within this model reflect program-
matic needs that will determine the sustainability of the programme into
the future (see Chapter 6). The model involves six components, clock-
wise in the hub of the wheel.
1. Assessment and periodic evaluation of the situation requires prev-
alence surveys of iodine status, including measurement of urinary
iodine levels and an analysis of the salt situation. Most countries have
completed this step, and now need to do periodic reassessment.
2. Dissemination of findings implies communication to health pro-
fessionals and the public, so that there is full understanding of the
IDD problem, the importance of using iodized salt and the potential
benefits of iodine deficiency elimination. This needs to be an ongoing
activity.
3. Planning: Development of a plan of action includes the establish-
ment of an intersectoral task force on IDD including the salt industry
and the formulation of a strategy document on achieving the elimi-
nation of IDD. The task force will need to remain active to ensure
programme sustainability.
4. Achieving political will requires intensive education and lobbying
of politicians and other opinion leaders on an ongoing basis.

8
2. IDD AND THEIR CONTROL, AND GLOBAL PROGRESS IN THEIR ELIMINATION

Figure 1 National IDD control programming cyclea

I, Me
r U TSH t. asu
ato natal in sal ce
i n i
d eoc
e l r a n Ide re ID
v ntif Dp
act te, n e le ssu y r
Imptre ra iodin ality A erage Ass popu evale
o i r u v ess la nc
g
TG, indica l and
t o Q t co sal tion a e (UI
sal t si )
s t r o z e d tua t risk
ces on odi tion
Pro ality C old i
Qu ouseh
H

Monitoring Assessment
evaluation

Communication
Requires: to health
• involvement of professionals and
salt industry Implementation Dissemination public on
of findings importance of
• training
benefits of IDD
• public education elimination

Achieving Planning
political will

Re
lob quires of a es ed;
b i
opi ying o ntens n a tioninclud involv
nio f p ive rdi at rs
n le olit ed
ade icia uca coo e th ecto e
rs o ns a tion n der k forc f all s privat
U tas s o d
f al nd o and e n
l le the
vel r IDD ntativ blic a
s e s e pu
r
rep

a
Adapted from BS Hetzel, 1994 (11).

5. Implementation needs the full involvement of the salt industry.


Special measures, such as negotiations for monitoring and quality
control of imported iodized salt, are required. It is also necessary to
ensure that iodized salt delivery systems reach all affected popula-
tions, including those in greatest need. In addition, the establishment
of cooperatives for small producers, or restructuring to larger units of
production, may be needed. Implementation requires training at all
levels in management, salt technology, laboratory methods, and com-
munication.
6. Monitoring and evaluation require the establishment of an effi-
cient system for the ongoing and routine collection of relevant data,
including measures of salt iodine quality assurance and household
use, and measures of programme performance.

9
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

The multidisciplinary orientation required for a successful programme


poses special difficulties in implementation. Experience indicates that
particular problems often arise between health professionals and the salt
industry – with their different professional orientations. There is need
for mutual education about the health and development consequences
of iodine deficiency, and about the problems encountered by the salt
industry in the continued production of high quality iodized salt. Such
teamwork is required in order to achieve sustainability.

2.3 Universal salt iodization (USI)


In 1994, a special session of the WHO and UNICEF Joint Committee
on Health Policy recommended USI as a safe, cost-effective, and sus-
tainable strategy to ensure sufficient intake of iodine by all individuals
(2). In nearly all countries where iodine deficiency occurs, it is now well
recognized that the most effective way to achieve the virtual elimination
of IDD is through USI.
USI involves the iodization of all human and livestock salt, including
salt used in the food industry. Adequate iodization of all salt will deliver
iodine in the required quantities to the population on a continuous and
self-sustaining basis.
The additional cost of iodine fortification in the process of salt pro-
duction should eventually be borne by the consumer, but is negligible.
This will greatly assist sustainability.
National salt iodization programmes are now implemented worldwide
and have followed a common pattern of evolution, which includes the
following phases:
• Decision phase: This phase involves making the decision for USI
supported by industry, backed by standards and regulation, and
supported by an implementation plan.
• Implementation phase: This phase ensures the infrastructure
for iodization and packaging of all human and livestock salt, and
supports that infrastructure with quality assurance measures, com-
munication and demand creation, regulation, and enforcement.
• Consolidation phase: Once the goal of USI is achieved, it needs
to be sustained and assessed through ongoing process and impact
monitoring, as well as periodic evaluation; the latter may include
international multidisciplinary teams.
A successful salt iodization programme depends upon the implementa-
tion of a set of activities at the national level by various sectors:

10
2. IDD AND THEIR CONTROL, AND GLOBAL PROGRESS IN THEIR ELIMINATION

• Government ministries (legislative and justice, health, industry,


agriculture, education, communication, and fi nance);
• Salt producers, salt importers and distributors, food manufactur-
ers;
• Concerned civic groups, including consumer associations; and
• Nutrition, food, and medical scientists, and other key opinion mak-
ers.
Opening the channels of communication and maintaining commitment
and cooperation across these various groups is perhaps the greatest chal-
lenge to reaching the IDD elimination goal and sustaining it for the long
term.
Salt producers and distributors are critical in ensuring that IDD is
eliminated. Protecting consumers requires that a framework be estab-
lished to ensure quality control of the production of iodized salt, as well
as the distribution of adequately packaged and labelled iodized salt. The
establishment of this framework is the main responsibility of the govern-
ment.
Ensuring a demand for the product and understanding the reason
for insisting upon only iodized salt is a shared responsibility of the pri-
vate sector and government. Establishment of iodization as the norm and
ensuring customer demand will determine the success and sustainability
of the programme.
USI, which ensures that all salt for human and animal consumption
is adequately iodized, has been remarkably successful in many coun-
tries. Over 30 countries have achieved the goal of USI (>90% of house-
holds using iodized salt), and many others are on track. Most countries
that have failed to achieve coverage over 20% have confl ict situations
that hinder all health efforts. In rare instances, it may happen that salt
iodization efforts are unable to meet the requirement of women during
pregnancy, exposing the progeny to potential developmental risks. In
such situations, while efforts to improve the salt iodization programme
continue, iodine supplementation may be considered for both pregnant
women and children less than two years of age as a daily oral dose of
iodine or a single oral dose of iodized oil every six to 12 months (6).
There is much evidence that correction of iodine deficiency has
been followed by a “coming to life” of a community suffering from the
effects on the brain of hypothyroidism due to iodine deficiency. Such
an increase in vitality is responsible for improved learning by school-
children, improved work performance of adults, and a better quality of
life. The economic significance of the prevention of iodine deficiency
disorders needs to be clearly understood (10). Education about these

11
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

basic facts has to be repeated, with the inevitable changes over time in
Ministries of Health and the public heath community and salt produc-
ers. Otherwise, a successful programme will lapse, as has occurred in a
number of countries.

2.4 Iodine supplementation


In some countries and areas with insufficient access to iodized salt for
vulnerable groups of the population, additional temporary strategies
need to be considered to ensure optimal iodine nutrition for these groups
while strengthening the salt iodization programmes to reach universal
coverage (12). In particular, each country should assess the current situ-
ation of its salt iodization programme to identify national or subnational
problems and to update its strategies and action plans. The most vul-
nerable groups, pregnant and lactating women, should be considered
for supplementation with iodine until the salt iodization programme is
scaled up. For children seven to 24 months of age, either supplementa-
tion or use of iodine-fortified complementary foods may be a possible
temporary public health measure.

Table 2 Recommended dosages of daily and annual iodine supplementation (6)


POPULATION DAILY DOSE OF IODINE SINGLE ANNUAL DOSE OF
GROUP SUPPLEMENT (µg/d) IODIZED OIL SUPPLEMENT (mg/y)

Pregnant women 250 400


Lactating women 250 400
Women of reproductive age (15–49 y) 150 400
Children < 2 ya,b 90 200
a
For children 0–6 months of age, iodine supplementation should be given through breast milk. This implies that the
child is exclusively breastfed and that the lactating mother received iodine supplementation as indicated above.
b
These figures for iodine supplements are given in situations where complementary food fortified with iodine is not
available, in which case iodine supplementation is required for children of 7–24 months of age.

2.5 Sustainability
The progress made with IDD programs in the past decade reflects pro-
gram maturation, and raises the question of how well these programs
will be sustained into the future. IDD cannot be eradicated in one great
global effort like smallpox and, hopefully, poliomyelitis, since these are
infectious diseases with only one host: man. Once eliminated, they can-
not come back. By contrast, IDD is a nutritional deficiency that is prima-
rily the result of deficiency of iodine in soil and water. IDD can therefore
return at any time after their elimination if program success is not sus-
tained. Indeed, there is evidence that iodine deficiency is returning to
some countries where it had been eliminated in the past (13).
Ideally, salt iodization programs ensure that there is adequate iodine

12
2. IDD AND THEIR CONTROL, AND GLOBAL PROGRESS IN THEIR ELIMINATION

intake for the entire population, and the cost of iodization is included
as part of the cost of doing business within the salt industry. The IDD
program in this case simply needs to monitor the situation.
In reality, even with mature salt iodization programs with high cover-
age, programs remain vulnerable to changes in the salt industry, chang-
es in political will, and changes in awareness or consumer acceptance.
Thus, it is important to monitor the overall programmatic indicators as
well as measures of salt iodization and impact to ensure that achieve-
ments are sustained.
Chapter 6 describes indicators of programme sustainability, includ-
ing programmatic indicators. These fall generally into two categories:
1) measures of achievement in salt iodization and iodine status; and 2)
measures of ongoing political support and programme strength.

Monitoring achievement
Sustainable programmes must have a monitoring system that provides
basic information about salt iodization, and about population iodine sta-
tus. This includes monitoring the proportion of households using iodized
salt adequate to meeting iodine intake needs, and assessing iodine sta-
tus through population-based median urinary iodine levels. Monitoring
needs to provide information on where problems may arise at different
levels in the salt iodization production and distribution system that might
contribute to less-than-optimal iodine status. This includes measures
of quality assurance at production facilities, or measures of compliance
with government requirements for imported salt.
When the monitoring system is robust, corrective measures are taken
to ensure that iodized salt use provides adequate intake, and this is con-
fi rmed by periodic population assessment, including understanding the
status of pregnant and lactating women.

Monitoring political support and program strength


Programmatic indicators have been used in the past to assess program
strength and political commitment. These indicators have been revised,
and are presented in Chapter 6. The indicators included reflect the
degree to which political commitment is present and likely to continue,
and different program elements critical to sustainability.
Sustainable programs should have mechanisms for oversight such
as a multisectoral coalition. They should have political commitment
reflected in budget allocation for program activities, and should have
established the legislative and regulatory environment for salt iodization.
There should be mechanisms for ongoing public education, and inclu-
sion of information on IDD in education curricula. There should be

13
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

strong partnership with the salt industry, with evidence of their partici-
pation reflected in sound quality assurance measures and absorption of
the cost of potassium iodate into the cost of doing business. And there
should be, as noted above, mechanisms for adequate monitoring of salt
and iodine status, periodic reporting, and establishment of an ongoing
national database to track sustained progress.
With these elements in place, and with achievement of high iodized
salt use, programs have reduced vulnerability, and are likely to be sus-
tained.

2.6 Global progress in the elimination of IDD


Between 1994 and 2006, the number of countries that carried out a uri-
nary iodine national survey increased to 94, and survey data on iodine
deficiency now covers 91.1% of the world population. There is still no
data for 63 countries, which together represent 8.9% of the world popu-
lation. Out of the 130 countries with estimates based on surveys at both
the national and subnational level, there are only 47 countries where IDD
still remains as a public health problem, compared to 54 in 2004 and 126
in 1993. Iodine intake (reflected by the median urinary iodine concen-
tration) in the other 83 countries is as follows: “adequate”1 or “above
recommended nutrient intakes”2 in 76 countries; and “excessive”3 in
seven countries. About 31% (1 900.9 million) of the world population
is estimated to have insufficient iodine intakes, with the most affected
WHO regions being South-East Asia and Europe (Table 3).
It is currently estimated that 70% of households throughout the world
have access to (and use) iodized salt (14).

2.7 Challenges for the future: consolidating the achievement


It is clear that, despite the great success in many countries, challenges
remain for the future.
• As programmes mature, ensuring their sustainability is critical (see
Chapter 6).
• Continued and strong government commitment and motivation,
with appropriate annual budgetary allocations to maintain the
process, are essential to eliminate IDD.
• The salt industry should have the capacity to implement effective
iodization, in particular with regard to compliance with the regula-
tions and monitoring of quality assurance.

1
UI between 100 µg/l and 199 µg/l
2
UI between 200 µg/l and 299 µg/l
3
UI above 300 µg/l

14
2. IDD AND THEIR CONTROL, AND GLOBAL PROGRESS IN THEIR ELIMINATION

Table 3 Proportion of population and number of individuals in the general


population (all age groups) with insufficient iodine intake by WHO
regions during the period between 1994 and 2006,a,b and proportion
of households using iodized saltc
WHO REGIONS INADEQUATE IODINE NUTRITION % HOUSEHOLD WITH
WITH ACCESS TO
d
PROPORTION (%) TOTAL NUMBER (MILLION) IODIZED SALT

Africa 41.5 312.9 66.6


Americas 11.0 98.6 86.8
South-East Asia 30.0 503.6 61.0
Europe 52.0 459.7 49.2
Eastern Mediterranean 47.2 259.3 47.3
Western Pacific 21.2 374.7 89.5
Total 30.6 1 900.9 70
a
Source: WHO global database on IDD: http://www.who.int/vmnis
b
Based on surveys from 130 countries made available to WHO and carried out between January 1994 and December
2006.
c
Country data on proportion of households using iodized salt based on UNICEF global database: http://www.
childinfo.org and the State of the World’s Children (SOWC) nutrition table http://www.unicef.org/sowc07/
statistics/statistics.php
d
UN population division. World population prospects: the 2004 revision. New York, United Nations, 2005.

• Monitoring systems should be in place to ensure specified salt


iodine content, and should be coordinated with effective regulation
and enforcement.
• Small-scale producers need to be included in this process to ensure
that their products are also brought up to standard and that they
deliver the right amount of iodine to the population. This is often
best achieved by the formation of cooperatives working with a com-
mon distributor or any other business models that reduce the need
for many small iodization units.
• The contribution of iodine from salt used in the food industry should
be considered and monitored in the IDD elimination effort.
• In some countries, salt for animal consumption has not been
included in the iodization programme and is not covered by leg-
islation. Animal productivity is also enhanced by elimination of
IDD. Ensuring this salt is iodized also means eliminating leakage
of non-iodized salt into the market and resultant use by the general
population.
• There are still numerous places in the world where iodized salt
is not available. Identifying these areas and developing in them a
market for iodized salt is critical to successful IDD elimination.
This process includes creating consumer awareness and demand.

15
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Ensuring the required daily intake of iodine to maintain normal brain


function is as important as the provision of clean water. There is ade-
quate knowledge and expertise to ensure the sustained elimination of
IDD from the entire world.

16
3 Indicators of the
salt iodization process

3.1 Factors that determine salt iodine content


Appropriate legislation and supportive regulations constitute the point
of departure, or cornerstone, of the salt iodization programme within a
country, providing the framework within which the salt iodization pro-
gramme functions. Regulations specify the iodine content that should be
in salt at the point of production for both human and animal consump-
tion. Ideally, they should also outline specific activities for internal and
external monitoring of the iodine in salt at the production or iodization
sites, and encourage the use of the titration method, or an equivalent
method, in order to provide precise measurements of the iodine content
in salt. Ultimately, the regulatory environment represents the primary
factor determining the iodine content of salt in any country.
Iodization of salt may take place inside the country at the main produc-
tion or packing sites, or outside the country for those countries import-
ing salt which has already been iodized. Salt is iodized by the addition of
fi xed amounts of potassium iodate (KIO3) or potassium iodide (KI), as
either a dry solid in a powder form or an aqueous solution, at the point of
production. The amount of iodine added to salt should be in accordance
with the regulation of the specific country where it will be used.
Iodate is recommended as fortificant in preference to iodide because it
is much more stable (15,16).1 The stability of iodine in salt and levels of
iodization are issues of crucial importance to national health authorities
and salt producers, as they have implications for programme effective-
ness, safety, and cost.
The actual availability of iodine from iodized salt at the consumer
level can vary over a wide range as a result of:

1
Potassium iodate and potassium iodide have a long-standing and widespread history
of use for fortifying salt without apparent adverse health effects. Potassium iodate has
been shown to be a more suitable substance for fortifying salt than potassium iodide
because of its greater stability, particularly in warm, damp, or tropical climates. In ad-
dition, no data are available indicating toxicological hazard from the ingestion of these
salts below the level of Provisional Maximum Tolerable Daily Intake or PMTDI (15).

17
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

• Variability in the amount of iodine added during the iodization


process;
• Uneven distribution of iodine in the iodized salt, within batches
and individual bags, due to insufficient mixing of salt after the salt
iodization process and/or variation in particle size of salt crystals in
a batch or bag;
• The extent of loss of iodine due to salt impurities, packaging, and
environmental conditions during storage and distribution;
• Loss of iodine due to food processing, and washing and cooking
processes in the household;
• The availability of non-iodized salt from unconventional marketing
sources.
In order to determine appropriate levels of iodization, an accurate esti-
mate within countries is required of the losses of iodine occurring under
local conditions between the time of iodization and the time of consump-
tion. Control of moisture content in iodized salt throughout manufac-
turing and distribution, by improved processing, packaging and storage,
is critical to the stability of the added iodine. Earlier estimates of losses
have proven to be too high. With adequate packaging, losses are minimal
under most conditions.
Iodized salt is usually distributed from the producer to the repackager,
wholesaler, or retailer either in 50 kg bulk bags, or in consumer packages
usually in 500 g or 1 kg polyethylene bags, although smaller or bigger
sized packaging may also be used in some countries. Considerable loss-
es of iodine (30–80%) resulting from high humidity and porous 50 kg
packaging can be significantly reduced by the use of woven high-density
polyethylene bags, with a continuous fi lm insert, or laminate of low-den-
sity polyethylene bags, which provides a good moisture barrier.
The loss of iodine in salt from 500 g or 1 kg good quality polyethylene
packaging appears to be less than previously thought. There is some
evidence that the loss of iodine from salt packaged in good quality small
polyethylene bags of about 75 to 80 micron thickness and containing
500 g salt, is generally less than 10% over an 18-month period, regard-
less of climatic conditions, fi ne or coarse texture, or whether the packag-
ing had been opened or not.1

Recommendations
WHO/UNICEF/ICCIDD (19) recommend that, in typical circum-
stances, where the iodine lost from salt is 20% from production site to

1
P Joost, personal communication, December 2006.

18
3. INDICATORS OF THE SALT IODIZATION PROCESS

household, another 20% is lost during cooking before consumption, and


average salt intake is 10 g per person per day, iodine concentration in salt
at the point of production should be within the range of 20–40 mg of iodine
per kg of salt (i.e., 20–40 ppm of iodine) in order to provide 150 µg of
iodine per person per day (17). In countries where iodized salt is used in
processed foods, the iodine content in salt should be closer to the lower
end of this range and vice versa. The iodine should preferably be added
as potassium iodate. Under these circumstances, median urinary iodine
levels are expected to vary from 100–199 µg/l.
However, in some instances the quality of iodized salt is poor, or the
salt is incorrectly packaged, or the salt deteriorates due to excessive long-
term exposure to moisture, heat, and contaminants. Iodine losses from
point of production to consumption can then be well in excess of 50%.
In addition, salt consumption is sometimes much less than 10 g per per-
son per day. As a result, actual iodine consumption may fall well below
recommended levels, leading to low urinary iodine values for the popula-
tion.
Regular surveys of median iodine urinary iodine levels should there-
fore be carried out in a nationally representative sample, along with
measurements of the iodine content in salt and other sources of iodine
in the diet to ensure that those levels are within the recommended range
(100–199 µg/l). If not, the level of iodization of salt, and factors affecting
the utilization of iodized salt, should be reassessed focusing on:
• The percentage of households using adequately iodized salt, i.e. salt
containing 15 to 40 ppm of iodine at the household level;
• Production-level quality assurance;
• Factors affecting the iodine content of salt such as packaging, trans-
port, and storage;
• Food habits in relation to salt intake and cooking practices.
National authorities should establish initial levels for iodization in con-
sultation with the salt industry, taking into account expected losses and
local salt consumption. Once iodization has commenced, regular sur-
veys of salt iodine content and urinary iodine levels should be carried out
to determine if the programme is having the desired effect.
Discussions and regulations about iodine levels in salt must clearly
specify whether they refer to total content of iodine alone or to content of
iodine compound (KIO3 or KI).
It is recommended that the level be expressed as content of iodine alone.
This approach emphasizes the physiologically important component
(iodine) and facilitates comparison of its different forms.

19
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Managing the iodized salt program in a country


For optimal management and functioning of the salt iodization pro-
gramme in a country, a governmental health official, a national mul-
tisectoral coalition including all the partners involved in IDD control
should take responsibility for coordinating and driving IDD-related
activities in a country. Ideally, salt producers should be integral members
of such commissions to jointly manage the various components of the
salt iodization programme along with other role players such as govern-
ment officials, international health agencies, consumer representatives,
researchers, academics, etc. (See Section 2.4 and Figure 1.)

3.2 Determining salt iodine levels


The iodine content of salt can be determined quantitatively with the
titration method, and qualitatively using rapid test kits. In addition to the
titration method, technology has advanced the possibilities of analysing
the iodine content of salt quantitatively using potentiometry or spectro-
photometry. A simple and portable single wavelength spectrophotometer
has recently been developed. These methods should yield similar quanti-
tative results and should therefore be seen as equivalent methods.
All of these methods have certain advantages and disadvantages
which generally influence the choice of method in specific circumstanc-
es. However, the titration method, which is by far the most commonly
used quantitative method, still remains the reference method for deter-
mining the iodine concentration in salt. When other methods are used,
it should be standardized against the titration method.
Facilities for titration are usually available in public health or food
standards laboratories. In addition, ideally it should be standard prac-
tice for salt producers to use the titration method to routinely check the
accuracy of their salt iodization at the site where salt is iodized. Titration
should preferably be carried out on-site.

Titration method
The titration method requires the use of a small laboratory equipped
with some basic instruments, such as a precision scale, a burette, glass-
ware, and pipettes. Additional equipment, such as a magnetic stirrer and
dispensers, will save time and optimize the analytical procedure.
Basically, iodine analysis by titration involves the preparation of four
solutions and a standard solution which will last for variable periods of
time, and then determining the iodine concentration in a salt solution
by adding the pre-made reagents/solutions followed by the titration step.
The iodine content of salt is determined by liberating iodine from salt and
titrating the iodine with sodium thiosulfate using starch as an external

20
3. INDICATORS OF THE SALT IODIZATION PROCESS

indicator. The method of liberating iodine from salt varies depending on


whether salt is iodized with iodate or iodide. Details of the method are
given in Annex 1. The procedure requires some training and laboratory
skills, which can be conveyed to salt producers during a training course.
Titration, or an equivalent method, is preferred for accurate testing
of salt batches produced in factories or upon their arrival in a country,
and in cases of doubt, contestation, etc. This method is recommended
for determining the concentration of iodine in salt at various levels of the
distribution system where such accurate testing is required, and for test-
ing when there are legal enforcement issues. Once the method is estab-
lished, it is necessary to adhere to proper internal and external quality
control measures.

Rapid test kits (RTK)


These are small 10–50 ml bottles containing a stabilized starch-based
solution. One drop of the solution dripped on a teaspoon of salt contain-
ing iodine produces a blue/purple colour change. Colouration indicates
that iodine is present. Different test kits are used depending on whether
the salt is iodized with potassium iodate or iodide. In cases where there
is suspicion of alkalinity in the salt sample, a ‘recheck solution’ is used.
A drop of this solution is applied fi rst, followed by the test solution (see
Annex 1 for further details).
Recent evaluations of these kits showed that the colour reaction can-
not be used as a quantitative indication of the iodine content (18). These
kits should therefore be regarded as qualitative rather than quantitative
and are most appropriate to indicate the presence or absence of iodine,
but not of the concentration.
An advantage of rapid test kits is that they can be used in the field to
give an immediate result. They are therefore useful to health inspectors
and others who are involved in carrying out spot checks on food quality
or household surveys. They may also play a valuable educational role, in
that they provide a visible indication that salt actually is iodized. Accord-
ingly, they can be used for demonstration purposes in schools and other
institutions. However, because rapid test kits do not give a reliable esti-
mate of iodine content (19,20), results must be backed up by titration.
There are a large number of test kits available on the market and many
countries are currently producing their own. These kits are of variable
quality and accuracy. UNICEF, with CDC and WHO, evaluated avail-
able test kits, and confi rmed that the quality of the kits is quite variable.
The evaluation resulted in recommendations for basic qualifications for
kits, including instructions in English, recommended sample weight or
size, shelf life, and directions for use.

21
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

National surveys to estimate the household coverage of adequately


iodized salt using rapid test kits alone will only be able to determine the
percentage of households using salt containing any iodine. However, in
order to make inferences about the household coverage of adequately
iodized salt, it is necessary to employ the quantitative titration method
for iodine analysis, either on all salt samples or on a sub-sample. For the
latter, a sub-sample of salt which has been analysed by the rapid test kit
should also be analysed using the titration method for quantification. In
this way, more reliable information on the adequacy of salt iodine and
its likelihood of providing adequate iodine intake is available for tracking
progress.

3.3 Indicators for monitoring at different levels


Ideally, monitoring the iodine content of salt should be conducted inter-
nally by the salt producer at the site of iodization, as well as externally
by the health authorities. Internal monitoring should be done routinely,
and external monitoring intermittently, and where feasible, both these
monitoring systems should use the titration method for determining the
iodine content of salt. The different steps of the monitoring process are
summarized in Figure 2.

Internal monitoring by producers and distributors


A critical indicator of adequate salt iodization is a measure of the quality
of iodized salt leaving production facilities. This may be reflected in a
proportion of samples meeting government standards, or samples plot-
ted regularly in a control chart to demonstrate that samples fall within
the acceptable range.
The Ministry of Industry, the Bureau of Standards, or Codex Alimen-
tarius are useful reference sources for guiding producers in the process
of iodizing salt. They can also establish the ultimate standards expected
in the production of iodized salt.
Adherence to these manufacturing standards is perhaps the most
important issue in the elimination of IDD. Therefore, the producer plays
a pivotal role both in improving the accuracy of the iodization process
and in reducing the considerable variations observed in iodine concen-
tration in many countries.
Among the areas of greatest concern is the very important mixing
or spraying step (21). This area not only includes the actual iodization
method chosen by a production or packaging facility, but also the assur-
ance that the producer closely adheres to the amount of time for mixing.
Salt samples taken from the production line should be regularly ana-
lysed by titration. The iodine concentration of each batch should be

22
Figure 2 A monitoring and evaluation system for salt iodization

Certificate of Quality
Food fortified with iodized salt Iodized salt (Food Control and
National or imported Customs)

Imported Internal monitoring Quality Control and Quality


Assurance (Dept. of Quality Control
fortified food (factories or packers) of Factories and Packers)
Certificate of Importation warehouse
Conformity or Factory Inspection (Corroborating
Inspection External monitoring REGULATORY MONITORING
trial) Technical Auditing (Government
(Corroborating (factories or packers) Food Control Unit)
trial) (Food
Control Dept. and

23
Customs) Commercial monitoring Verification of Legal Compliance
(Food Control and Units of Standards
(at retail stores)
and/or Consumer Protection)
Quality auditing with
conformityAssessment
(Food Control/witnesses)

Household/individual Assessment of acccess,


3. INDICATORS OF THE SALT IODIZATION PROCESS

monitoring utilization and coverage


HOUSEHOLD/INDIVIDUAL
Monitoring and evaluation
Assessment of impact on
Impact evaluation
consumption, biochemicals,
(individuals, households) clinical and functional outcomes

Adapted from L. Allen (17).


ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

checked at least once. Rapid test kits can be used more frequently to
check that the addition of iodine has not been interrupted.
It is recommended that wherever possible adequate staff at a produc-
tion plant should be trained and their skills standardized to determine
the iodine concentration accurately using the titration method. Fur-
thermore, key persons at each production site, including the managers,
should be aware of the detrimental consequences of iodine deficiency
and excess, as well as the health benefits of correctly iodized salt.
Results should be recorded and plotted in a quality assurance chart.
When levels are not satisfactory, immediate corrective action should be
taken and that action entered into the record book.
Because production methods and factory sizes vary so widely, it is
beyond the scope of this manual to defi ne this process in any greater
detail. Whatever the method adopted, the process, combined with exter-
nal quality assurance measures, should result in salt that has an iodine
level within the upper and lower range established by regulations. In
other words, internal and external quality control should ensure that the
level of iodine is in the range stipulated by national regulations, that is
both effective to control iodine deficiency and safe with regard to exces-
sive iodine intake.
When importers and distributors procure salt, they have the respon-
sibility to either ensure that it meets specifications as stipulated in the
requirements, or to ensure that these are met before salt goes out to the
wholesale or retail market. This implies that they should have a quality
assurance system that includes salt iodine titration measurements.
If the salt they receive is not up to standard, they will need to have
their own iodization facility. All salt should be distributed in polyethyl-
ene bags with appropriate labels.

External monitoring by governments


Legislation and regulations establish the authority of the government to
ensure that iodized salt meets government standards, and external monitor-
ing by the government is done under the guidance of relevant regulations.
Governments must have some method of periodically checking that
salt producers are maintaining adequate quality assurance measures,
and that salt leaving production facilities meets government standards.
The main indicator for this level of monitoring is the proportion of sam-
ples taken that fall within the accepted range for iodine content. In addi-
tion, there may be a need for monitoring at the retail level to assess the
presence of counterfeit salt or salt not meeting standards in the market-
place. Capacity for retail monitoring varies, and the purpose may be
for checking the availability of different types of salt in the market or

24
3. INDICATORS OF THE SALT IODIZATION PROCESS

for advocacy, rather than providing a robust proportion as is done with


household sampling.
External monitoring is based upon the establishment of a law which
mandates that all salt for human and – in many countries, animal – con-
sumption is iodized. Details of implementation, inspection, and enforce-
ment are usually set out in the regulations. Guidelines for developing
regulations are available (22). It is crucial to state in the regulations the
amount of iodine as potassium iodate or potassium iodide to be added at
the point of production.
Other legal requirements covered in regulations should include pack-
aging in polyethylene bags, labelling to identify the iodine level, and the
name and address of the company packaging the salt. The regulation
also needs to designate a government agency or department which will
be responsible for a system of licensing producers, importers, and dis-
tributors, and inspecting their facilities.
That agency must also be responsible for periodically checking the
quality assurance records that must be kept, and for spot-checking the
salt for iodine content. Several monitoring and inspection systems have
emerged in different countries.
Often this monitoring becomes a function of the Food and Drugs
Bureau of the Health Ministry. In other countries, the Ministry of
Industry, or Mines, or Agriculture has this responsibility. In the case of
importation of salt, the Customs Authority is often in charge of checking
the specifications in the importation document, and in some circum-
stances taking samples to check the iodine level in the salt.
As indicated above, the salt testing kits that are used by these govern-
ment agencies should not be used in enforcement at the production level,
as they often give both false positive and false negative results and the
colour does not always accord well with titration. Government inspec-
tion systems need to have access to and use of salt titration in a standard-
ized laboratory on a regular basis.
When countries fi rst began to introduce salt iodization, inspection
systems were used largely to guide salt iodization programme managers
in identifying problems with salt iodization, and were rarely used for
enforcement purposes. As countries increase the coverage to 50%, these
systems should be strengthened and used for enforcement against those
producers who fail to comply with the law.
It is often the less expensive non-iodized salt in the market that pre-
vents the realization of the elimination of IDD. Indeed, as coverage of
iodized salt increases, special efforts need to be made to identify the
non-compliant importer, producer and distributor and systematically
eliminate that problem. To this end, a national register of all salt pro-

25
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

ducers supplying iodized salt to the market and of distributors/traders


of iodized salt will enhance the interaction with health authorities and
will create the opportunity of efficient external monitoring and mutual
exchange of relevant IDD information in an effort to strengthen the salt
iodization programme. These measures provide a ‘level playing field’ for
producers complying with the law.
Salt must be iodized indefi nitely, or until it is demonstrated that an
adequate iodine intake is available from other sources. The infrastruc-
ture, together with the annual budget to support the government inspec-
tion system, must be permanently established. In order to guarantee this,
it is essential that inspection and collection of iodized salt samples be
integrated into the existing food inspection system in the country. The
contact between the health authority and the salt producers could be
used to inform and educate the producer about IDD and the need for
optimal iodization of salt. Feedback of salt iodine results are an impor-
tant component of this interaction.

Monitoring at the household level


Just as knowing whether salt leaving production facilities is adequately
iodized, knowing whether consumers are using that salt is critical to a
programme’s success. The main indicator for assessing household use is
the proportion of households using salt with adequate iodine. This indi-
cator must accurately reflect the situation for the population sampled,
and the level of iodine in the salt sampled.
In the past, rapid test kits have been used to assess household cover-
age, whether used in surveys or in other data collection activities. Results
were presented as the percentage of households using salt with no iodine
and the percentage using ‘adequately’ iodized salt. However, the ability
of the rapid test kits to distinguish ‘adequately’ iodized salt has since
been recognized as limited, and titration is recommended for at least a
sub-sample of salt samples used in monitoring at the household level.
Household level monitoring methods are described in Chapter 5.
Household monitoring is usually done through surveys or other com-
munity-based methods.
For use with cross-sectional surveys, a household questionnaire con-
cerning the use of iodized salt and qualitative testing of that salt using a
rapid test kit has been employed successfully to determine overall cover-
age of iodized salt and to identify geographical gaps in the programme.
However, it must be emphasized that where rapid test kits are used alone,
it will only be possible to report on the proportion of households using
salt with any iodine, and not the proportion using ‘adequately’ iodized
salt, as has been done in the past.

26
3. INDICATORS OF THE SALT IODIZATION PROCESS

Questions on iodized salt use and salt testing have been included in the
UNICEF Multiple Indicator Cluster Surveys (MICS) and in the Demo-
graphic and Health Surveys. Some countries have successfully added
household salt testing to other national surveys, e.g., to either nutrition
surveys or surveys that collect key economic and census data. These sur-
veys provide estimates of the proportion of the population with iodized
salt coverage, and identify areas where there is low use of iodized salt
and/or where all the salt is non-iodized.
National surveys can be costly, and a community-based method may
be possible on a more regular basis. This approach may be organized in
the community or through the schools, particularly in areas with high
rates of school enrolment. Providing salt testing kits to environmental
health officers, community midwives, nutrition officers, schoolteach-
ers, mayors, and other government workers responsible for community
health, has been helpful in this process. These approaches are very effec-
tive communication and awareness tools, particularly when this aware-
ness is linked to action. This action could involve approaching the salt
producers or distributors and directly requesting them to supply iodized
salt.
Depending on the sampling methods and survey design adopted, it
may be possible for monitoring at the household level to provide results
that allow for visual representation of variations of coverage and provide
a basis for targeting resources and focusing interventions in areas where
they are most needed. Monitoring at this level should be followed by
specific action to identify further reasons for low iodized salt usage, and
should result in a range of actions to correct the problem.
Finally, the occurrence of parallel markets of non-iodized salt has
frequently been a barrier to achieving USI. National cross-sectional
household surveys and community monitoring have often been useful
in identifying such salt and in developing strategies to address the prob-
lem.

27
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

4 Indicators of impact

4.1 Overview
Assessment of thyroid size by palpation is the time-honoured method
of assessing IDD prevalence. However, because of the lack of sensitivity
to acute changes in iodine intake, this method is of limited usefulness
in assessing the impact of programmes once salt iodization has com-
menced. In this case, urinary iodine is the most useful indicator because
it is reflective of the current intake of iodine in the diet (23).
Since most countries have now started to implement IDD control pro-
grammes, urinary iodine rather than thyroid size is emphasized in this
manual as the principal indicator of impact. Thyroid size is more useful
in baseline assessments of the severity of IDD, and also has a role in the
assessment of the long-term impact of control programmes.
The introduction of ultrasonography for the assessment of thyroid
size has been a significant development. In areas of mild to moderate
IDD, measurement of thyroid volume using ultrasound is preferable to
palpation for grading goitre. New international reference values for thy-
roid volume by ultrasound have recently become available and can be
used for goitre screening in the context of IDD monitoring (24).
Two other indicators are included in this chapter: thyroid stimulating
hormone (TSH), and thyroglobulin (Tg). While TSH levels in neonates
are particularly sensitive to iodine deficiency, and although difficulties in
interpretation remain, there is a potential future for the use of neonatal
TSH in the identification of IDD and their control; although the cost of
implementing a TSH screening programme is too high for most devel-
oping countries. Measurement of Tg in children is a sensitive indicator
of iodine status and improving thyroid function after iodine repletion. A
standardized dried blood spot Tg assay has been developed and can be
used for assessing and monitoring iodine nutrition in the field (25).

4.2 Urinary iodine


Biological features
Most iodine absorbed in the body eventually appears in the urine. There-
fore, urinary iodine excretion is a good marker of very recent dietary

28
4. INDICATORS OF IMPACT

iodine intake. In individuals, urinary iodine excretion can vary some-


what from day to day and even within a given day. However, this varia-
tion tends to even out among populations.
Studies have convincingly demonstrated that a profi le of iodine con-
centrations in morning or other casual urine specimens (child or adult)
provides an adequate assessment of a population’s iodine nutrition, pro-
vided a sufficient number of specimens are collected. Round the clock
urine samples are difficult to obtain and are not necessary.
Relating urinary iodine to creatinine, as has been done in the past,
is cumbersome, expensive, and unnecessary. Indeed, urinary iodine/
creatinine ratios are unreliable, particularly when protein intake – and
consequently creatinine excretion – is low.

Feasibility
Acceptance of this indicator is very high, and casual urine specimens are
easy to obtain. Urinary iodine assay methods are not difficult to learn
or use, but meticulous attention is required to avoid contamination with
iodine at all stages. Special laboratory areas, glassware, and reagents
should be set aside solely for this determination.
In general, only small amounts (0.5–1.0 ml) of urine are required,
although the exact volume depends on the method. Some urine should
also be kept in reserve for replicate testing or for external quality con-
trol. Samples are collected in small cups and transferred to tubes, which
should be tightly sealed with screw tops. They do not require refrigera-
tion, addition of preservative, or immediate determination in most meth-
ods. They can be kept in the laboratory for months or more, preferably
in a refrigerator to avoid unpleasant odour.
Evaporation should be avoided, because this process artificially
increases the concentration. Samples may safely be frozen and refrozen,
but must be completely defrosted before aliquots are taken for analysis.
Many analytical techniques exist, varying from very precise measure-
ment with highly sophisticated instruments, to semi-quantitative ‘low
tech’ methods that can be used in regional, country, or local laborato-
ries. Most methods depend on iodine’s role as a catalyst in the reduction
of ceric ammonium sulfate (yellow colour) to the cerous form (colour-
less) in the presence of arsenious acid (the Sandell-Kolthoff reaction). A
digestion or other purification step using ammonium persulfate or chlo-
ric acid is necessary before carrying out this reaction, to rid the urine of
interfering contaminants.
A brief description of some of the methods introduced in this section
is presented in the following pages.

29
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Methods with ammonium persulfate (method A)


Small samples of urine (0.25–0.5 ml) are digested with ammonium per-
sulfate at 90–110 °C; arsenious acid and ceric ammonium sulfate are
then added. The decrease in yellow colour over a fi xed time period is
then measured by a spectrophotometer and plotted against a standard
curve constructed with known amounts of iodine (26). This method
requires a heating block and a spectrophotometer, which are both inex-
pensive instruments. About 100–150 subject samples can be run in a day
by one experienced technician. Several versions of this method exist and
details of one of these are given in Annex 3.

Methods with chloric acid (method B)


Chloric acid can be substituted for ammonium persulfate in the diges-
tion step, and the colorimetric determination carried out as for method
A (27). A disadvantage is the safety concern, because the chemical mix-
ture can be explosive if residues dry in ventilating systems. Handling
these chemicals in a fume cupboard and using a chloric acid trap when
performing sample digestion is strongly recommended (see Annex 3).

Other methods
A modification of method B uses the redox indicator ferroin and a stop-
watch instead of a spectrophotometer to measure colour change (28).
Urine is digested with chloric acid and colour changes in batches of sam-
ples measured relative to standards of known iodine content. This places
samples in categories (e.g., below 50 µg/l, 50–100 µg/l, 100–200 µg/l,
etc.) that can be adjusted to desired levels. This method is currently
being adapted to ammonium persulfate digestion.
Another, semi-quantitative method is based on the iodide-catalysed
oxidation of 3,3’,5,5’-tetramethylbenzidine by peracetic acid/H 2O2 to
yield coloured products that are recognized on a colour strip indicating
three ranges: <100 µg/l, 100–300 µg/l, and >300 µg/l (29). Interfering
substances are removed by pre-packed columns with activated charcoal.
Analyses must be run within two hours, and the procedure requires the
manufacturer’s pre-packed columns.
In still another method, samples are digested with ammonium persul-
fate on microplates enclosed in specially designed sealed cassettes and
heated to 110 °C (30). Samples are then transferred to another micro-
plate and the ceric ammonium sulfate reduction reaction carried out and
read on a microplate reader. Field tests are promising: up to 400 urine
samples can be analysed in one day, depending on manufacturers’ sup-
plies.

30
4. INDICATORS OF IMPACT

Choice of method
Criteria for assessing urinary iodine methods are reliability, speed, tech-
nical demands, complexity of instrumentation, independence from sole-
source suppliers, availability of high quality reagents, safety, and cost.
The choice among the above and other methods depends on local needs
and resources. Large central laboratories processing many samples may
prefer ‘high-tech’ methods, while smaller operations closer to the field
may fi nd the simplest methods more practical.
Due to the potential hazards of chloric acid, method A (see Annex 3)
using ammonium persulfate is currently recommended. It can adequate-
ly replace the chloric acid method, since the main difference is the sub-
stitution of ammonium persulfate for chloric acid in the digestion step.
Results are comparable.
The other methods described above show promise but are not yet
fully tested.

Quality control and reference laboratories


All laboratories should have clearly defi ned internal quality control pro-
cedures in place, and should be opened to external audit. In addition, all
laboratories should participate in an external quality control programme
in conjunction with a recognized reference laboratory. This is impor-
tant because unrecognized iodine contamination has been a common
occurrence in UI laboratories. An international network of resource lab-
oratories (IRLI1) was established to fi ll this need. It closely collaborates
with the Programme for Ensuring the Quality of Iodine Procedures
(EQUIP) run by the Centers for Disease Control of the United States
of America.2
Active efforts are now in progress, both to define performance criteria
for laboratories and to develop a global system of reference laboratories.
These reference laboratories will provide reliable measurements of urinary
iodine, and will conduct technical training and supervision. This initia-
tive is a major priority for ensuring sustainability of iodine sufficiency.

1
IRLI Network was jointly established by CDC, WHO, UNICEF, ICCIDD and MI to
identify laboratories to serve as effective resources for their regions, thus strengthening
the capacity of laboratories throughout the world to accurately measure iodine in urine
and salt. The network currently includes 12 laboratories (Australia, Belgium, Bulgaria,
Cameroon, China, Guatemala, India, Indonesia, Kazakhstan, Peru, the Russian Fed-
eration, South Africa). http://iodinenetwork.net/Resources_Lab.htm
2
EQUIP uses laboratory quality assurance as a tool for eliminating IDD worldwide.
It is a CDC standardization program designed to provide urinary iodine laboratories
with an independent assessment of their analytical performance. The program assists
laboratories to monitor the degree of variability and bias in their urinary iodine assay.
IRLI laboratories are invited to participate in the EQUIP program. http://www.cdc.
gov/nceh/globalhealth/projects/labactivites.htm

31
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Performance
Most of the above methods perform reliably, although some of the newer
ones need further testing as of this date. With appropriate dilutions, they
can be extended upward to examine whatever range is desired. The coef-
ficient of variation is generally under 10% for all methods. Proper train-
ing is necessary but not complicated.
Since casual specimens are used, it is desirable to measure a suffi-
cient number from a given population to allow for varying degrees of
subject hydration and other biological variations among individuals, as
well as to obtain a reasonably narrow confidence interval (see Annex 4).
In general, 30 urine determinations from a defi ned sampling group are
sufficient.

Interpretation
Simple modern methods make it feasible to process large numbers of
samples at a low cost and to characterize the distribution according to
different cut-off points and intervals. The cut-off points proposed for
classifying iodine nutrition into different degrees of public health signifi-
cance are shown in Table 4 and Table 5.
The median value for the sampled population is the most commonly
assessed indicator. Urinary iodine values from populations are usually
not normally distributed. Therefore, the median rather than the mean
should be used as the measure of central tendency. Likewise, percentiles
rather than standard deviations should be used as measures of spread.
Frequency distribution curves can also be very useful for full interpreta-
tion, particularly if there is salt iodine level data available for the same
population.
In children and non-pregnant women, median urinary iodine con-
centrations of between 100 µg/l and 299 µg/l defi ne a population which
has no iodine deficiency.1 In addition, not more than 20% of samples
should be below 50 µg/l. In non-pregnant, non-lactating women, a uri-
nary iodine concentration of 100 µg/l corresponds roughly to a daily
iodine intake of about 150 µg under steady-state conditions.
During pregnancy, median urinary iodine concentrations of between
150 µg/l and 249 µg/l defi ne a population which has no iodine deficiency
(6).
Establishing the ideal range of values for urinary iodine is difficult.
Historically, schoolchildren were assessed by palpation, establishing a
pre-intervention baseline for the prevalence of IDD. This population

1
By defi nition, when the median is 100 µg/l, at least 50% of the samples will be lower
than 100 µg/l.

32
4. INDICATORS OF IMPACT

Table 4 Epidemiological criteria for assessing iodine nutrition based on


median urinary iodine concentrations of school-age children
(≥6 years) a
MEDIAN URINARY IODINE INTAKE IODINE STATUS
IODINE (µg/l)

< 20 Insufficient Severe iodine deficiency


20–49 Insufficient Moderate iodine deficiency
50–99 Insufficient Mild iodine deficiency
100–199 Adequate Adequate iodine nutrition
200–299 Above requirements Likely to provide adequate intake for pregnant/lactating
women, but may pose a slight risk of more than
adequate intake in the overall population
≥300 Excessive Risk of adverse health consequences (iodine-induced
hyperthyroidism, autoimmune thyroid diseases)
a
Applies to adults, but not to pregnant and lactating women.

Table 5 Epidemiological criteria for assessing iodine nutrition based on


the median or range in urinary iodine concentrations of
pregnant womena
POPULATION GROUP MEDIAN URINARY IODINE IODINE INTAKE
CONCENTRATION (µg/l)

Pregnant women < 150 Insufficient


150–249 Adequate
250–499 Above requirements
≥ 500 Excessiveb
a
For lactating women and children <2 years of age a median urinary iodine concentration of 100 µg/l can be used to
define adequate iodine intake, but no other categories of iodine intake are defined. Although lactating women have
the same requirement as pregnant women, the median urinary iodine is lower because iodine is excreted in breast
milk (6).
b
The term “excessive” means in excess of the amount required to prevent and control iodine deficiency.

was also sampled for urinary iodine, thus establishing a normal range.
This normal range has been extrapolated to the full population. It may
be more logical to sample women of reproductive age, or adolescent girls
– thus providing more information on populations that may include
those with or on the verge of greater need. The upper limit of the recom-
mended range for these populations reflects concern about the risk of
hyperthyroidism when high levels are introduced to a previously endem-
ic population.
Recent data have suggested that the normal range for pregnant and
lactating women should reflect their additional need and the risk that
these needs may not be met if population levels are too low. However,
this leaves a relatively narrow range for a median UI level that will both
meet the needs for pregnant/lactating women, and not be excessive for

33
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

the remainder of the population. This guide provides the best current
estimates for the optimal values to meet the overall population needs.
Urinary iodine concentration is currently the most practical biochem-
ical marker for iodine nutrition when carried out with appropriate tech-
nology and sampling. This approach assesses iodine nutrition only at the
time of measurement, whereas thyroid size reflects iodine nutrition over
months or years. Therefore, even though populations may have attained
iodine sufficiency on the basis of median urinary iodine concentration,
goitre may persist, even in children.
With rapid global progress in correcting iodine deficiency, examples
of iodine excess are being recognized, particularly when salt iodization
is excessive and poorly monitored (20). Tolerance to high doses of iodine
is quite variable, and many individuals ingest amounts of several milli-
grams or more per day without apparent problems. The major epidemio-
logical consequence of iodine excess is iodine-induced hyperthyroidism
(IIH) (24,31). This occurs more commonly in older subjects with pre-
existing nodular goitres, and may occur even when iodine intake is with-
in the normal range.
Iodine intakes above 300 µg/l per day should generally be discouraged,
particularly in areas where iodine deficiency has previously existed. In
these situations, more individuals may be vulnerable to adverse health
consequences, including iodine-induced hyperthyroidism and autoim-
mune thyroid diseases.
In populations characterized by long-standing iodine deficiency
and a rapid increase in iodine intake, median values for urinary iodine
above 200 µg/l (and in pregnant women, above 250 µg/l) are not recom-
mended because of the possible risk of iodine-induced hyperthyroidism.
This adverse condition can occur during the 5 to 10 years following the
introduction of iodized salt (24,31). Beyond this period of time, median
values up to 300 µg/l have not demonstrated side-effects, at least not
in populations with adequately iodized salt. In schoolchildren, urinary
iodine concentrations >500 µg/l are associated with increasing thyroid
volume, which reflects the adverse effects of chronic iodine excess (32).

4.3 Thyroid size


The traditional method for determining thyroid size is inspection and
palpation. Ultrasonography provides a more precise and objective meth-
od.
Both methods are described below. Issues common to palpation and
ultrasound are not repeated in the section on ultrasound.

34
4. INDICATORS OF IMPACT

4.3.1 Thyroid size by palpation


The size of the thyroid gland changes inversely in response to altera-
tions in iodine intake, with a lag interval that varies from a few months
to several years, depending on many factors. These include the severity
and duration of iodine deficiency, the type and effectiveness of iodine
supplementation, age, sex, and possible additional goitrogenic factors.
The term “goitre” refers to a thyroid gland that is enlarged. The state-
ment that “a thyroid gland each of whose lobes have a volume greater
than the terminal phalanges of the thumb of the person examined will be
considered goitrous” is empiric, but has been used in most epidemiologi-
cal studies of endemic goitre and is still recommended (see Table 6).

Feasibility
Palpation of the thyroid is particularly useful in assessing goitre preva-
lence before the introduction of any intervention to control IDD, but
much less so in determining impact. Costs are associated with mounting
a survey, which is relatively easy to conduct, and training of personnel.
These costs will vary depending upon the availability of health care per-
sonnel, accessibility of the population, and sample size. Feasibility and
performance vary according to target groups, as follows:
Neonates: It is neither feasible nor practical to assess goitre among
neonates, whether by palpation or ultrasound. Performance is poor.
School-age children (6–12 years): This is the preferred group, as
it is usually easily accessible. However, the highest prevalence of goitre
occurs during puberty and childbearing age. Some studies have focused
on children 8 to 10 years of age.
There is a practical reason for not measuring very young age groups.
The smaller the child, the smaller the thyroid, and the more difficult it
is to perform palpation.
If the proportion of children attending school is low, schoolchildren
may not be representative (Annex 4). In these cases, spot surveys should
be conducted among those who attend school and those who do not, to
ascertain if there is any significant difference between the two.
Alternatively, children can be surveyed in households. For further dis-
cussion, see Chapter 5 on survey methods.
Adults: Pregnant and lactating women are of particular concern. Preg-
nant women are a prime target group for IDD control activities because
they are especially sensitive to marginal iodine deficiency. Often they are
relatively accessible given their participation in antenatal clinics. Women
of childbearing age – 15 to 44 years – may be surveyed in households.

35
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Technique
The subject to be examined stands in front of the examiner, who looks
carefully at the neck for any sign of visible thyroid enlargement. The
subject is then asked to look up and thereby to fully extend the neck.
This pushes the thyroid forward and makes any enlargement more
obvious.
Finally, the examiner palpates the thyroid by gently sliding their
own thumb along the side of the trachea (wind-pipe) between the
cricoid cartilage and the top of the sternum. Both sides of the trachea
are checked. The size and consistency of the thyroid gland are carefully
noted.
If necessary, the subject is asked to swallow (e.g. some water) when
being examined – the thyroid moves up on swallowing. The size of each
lobe of the thyroid is compared to the size of the tip (terminal phalanx)
of the thumb of the subject being examined.1 Goitre is graded according
to the classification presented in Table 6.

Table 6 Simplified classification of goitrea by palpation


Grade 0 No palpable or visible goitre
Grade 1 A goitre that is palpable but not visible when the neck is in the normal position (i.e., the
thyroid is not visibly enlarged)
Thyroid nodules in a thyroid which is otherwise not enlarged fall into this category
Grade 2 A swelling in the neck that is clearly visible when the neck is in a normal position and is
consistent with an enlarged thyroid when the neck is palpated
a
A thyroid gland will be considered goitrous when each lateral lobe has a volume greater than the terminal phalanx
of the thumbs of the subject being examined.

The specificity and sensitivity of palpation are low in grades 0 and 1 due
to a high inter-observer variation. As demonstrated by studies of experi-
enced examiners, misclassification can be high.

Interpretation
Table 7 gives the epidemiological criteria for establishing IDD severity,
based on goitre prevalence in school-age children. The terms mild, mod-
erate, and severe are relative and should be interpreted in context with
information from other indicators.

1
Another method is to stand behind the subject with the neck in the neutral position and
hold the fi ngers (not thumb) over the area of the gland. The person is asked to swallow
and the gland is palpated by the fi ngers as it glides up. This is repeated on each side of
the neck.

36
4. INDICATORS OF IMPACT

It is recommended that a total goitre rate or TGR (number with goitres


of grades 1 and 2 divided by total examined) of 5% or more in school-
children 6 to 12 years of age be used to signal the presence of a public
health problem. This recommendation is based on the observation that
in normal, iodine-replete populations, the prevalence of goitre should be
quite low. The cut-off point of 5% allows both for some margin of error
of goitre assessment, and for goitre that may occur in iodine-replete pop-
ulations due to other causes such as goitrogens and autoimmune thyroid
diseases.

Table 7 Epidemiological criteria for assessing the severity of IDD based on


the prevalence of goitre in school-age childrena
DEGREES OF IDD, EXPRESSED AS PERCENTAGE OF THE TOTAL OF THE NUMBER
OF CHILDREN SURVEYED

Total goitre rate (TGR) None Mild Moderate Severe


0.0–4.9% 5.0–19.9% 20.0–29.9% ≥ 30%
a
Goitre prevalence responds slowly to changes in iodine intake.

Finally, in this context it is emphasized that thyroid size in the com-


munity may not return to normal for months or years after correction of
iodine deficiency.

4.3.2 Thyroid size by ultrasonography


In areas of mild to moderate IDD, the sensitivity and specificity of palpa-
tion are poor and measurement of thyroid size using ultrasound is pref-
erable. Ultrasonography is a safe, non-invasive, specialized technique
that can be quickly done (2–3 minutes per subject) and is feasible even
in remote areas using portable equipment. Ultrasonography provides a
more precise measurement of thyroid volume compared with palpation.
This becomes especially significant when the prevalence of visible goi-
tres is small, and in monitoring iodine control programmes where thy-
roid volumes are expected to decrease over time. The technical aspects
of thyroid ultrasonography are reported in Annex 2.

Feasibility
Portable (weight 12–15 kg) ultrasound equipment with a 7.5 MHz
transducer currently costs about US $15 000. A source of electricity is
needed, and the operator needs to be specially trained in the technique.
Differences in technique (e.g. the pressure applied with the transducer)
and estimation of thyroid anatomy (e.g. inclusion of the thyroid isthmus
and/or capsule thickness) can result in high inter-observer variability.

37
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Interpretation
Results of ultrasonography from a study population should be compared
with reference data (33). Reference values for thyroid volume measured
by ultrasonography in schoolchildren of iodine-sufficient populations
are shown in Table 8. These are presented as a function of age, sex, and
body surface area (BSA) in order to take into account the differences in
body development among children of the same age in different countries.
This approach is potentially useful in countries with a high prevalence
of child growth retardation due to malnutrition with both stunting (low
height-for-age) and underweight (low weight-for-age).
An advantage of the thyroid volume-for-BSA is that the age of the
child is not required, which in some populations is not known with cer-
tainty. A limitation of the thyroid volume-for-BSA is that it requires the
collection of weights and heights: in severely malnourished populations
of schoolchildren, 10% or more may have a BSA below the lowest BSA
cut-off of 0.7.
The thyroid volume references proposed here are applicable for goi-
tre screening only if thyroid volume is determined by the standardized
method described in Annex 2.

Table 8 Gender-specific 97th percentile (P97) of thyroid volume (ml) by age


and body surface area (BSA) measured by ultrasound in iodine-
sufficient 6–12 year-old childrena
BOYS GIRLS BOYS GIRLS
AGE (y) P97 P97 BSA (m2) P97 P97

6 2.91 2.84 0.7 2.62 2.56


7 3.29 3.26 0.8 2.95 2.91
8 3.71 3.76 0.9 3.32 3.32
9 4.19 4.32 1.0 3.73 3.79
10 4.73 4.98 1.1 4.20 4.32
11 5.34 5.73 1.2 4.73 4.92
12 6.03 6.59 1.3 5.32 5.61
1.4 5.98 6.40
1.5 6.73 7.29
1.6 7.57 8.32
a
MB Zimmermann, 2004 (33).

4.4 Blood constituents


Two blood constituents, TSH and Tg, can serve as surveillance indica-
tors. In a population survey, blood spots on fi lter paper or serum samples
can be used to measure TSH and/or Tg.

38
4. INDICATORS OF IMPACT

Determining serum concentrations of the thyroid hormones, thyroxin


(T4) and triiodothyronine (T3), is usually not recommended for moni-
toring iodine nutrition, because these tests are more cumbersome, more
expensive, and less sensitive indicators.
In iodine deficiency, the serum T4 is typically lower and the serum T3
higher than in normal populations. However, the overlap is large enough
to make these tests impractical for ordinary epidemiological purposes.

4.4.1 Thyroid stimulating hormone (TSH)


Biological features
The pituitary secretes TSH in response to circulating levels of T4. Serum
TSH rises when serum T4 concentrations are low, and falls when they
are high. Iodine deficiency lowers circulating T4 and raises the serum
TSH, so iodine-deficient populations generally have higher serum TSH
concentrations than do iodine-sufficient groups.
However, the difference is not great and much overlap occurs between
individual TSH values. Therefore, the blood TSH concentration
in school-age children and adults is not a practical marker for iodine
deficiency, and its routine use in school-based surveys is not recom-
mended.
In contrast, TSH in neonates is a valuable indicator for iodine defi-
ciency. The neonatal thyroid has a low iodine content compared to that of
the adult, and hence iodine turnover is much higher. This high turnover,
which is exaggerated in iodine deficiency, requires increased stimulation
by TSH. Hence, TSH levels are increased in iodine-deficient popula-
tions for the fi rst few weeks of life – this phenomenon is called transient
hyperthyrotopinemia (25).
The prevalence of neonates with elevated TSH levels is therefore a
valuable indicator of the severity of iodine deficiency in a given popula-
tion. It has the additional advantage of highlighting the fact that iodine
deficiency directly affects the developing brain.
In iodine-sufficient populations, about one in 4000 neonates has con-
genital hypothyroidism, usually because of thyroid dysplasia. Prompt
correction with thyroid hormone is essential to avoid permanent mental
retardation.
Thyroid hormone affects proper development of the central nervous
system, particularly its myelination; a process that is very active in the
perinatal period. To detect congenital hypothyroidism and initiate rap-
id treatment, most developed countries conduct universal screening of
neonates with bloodspot TSH taken on fi lter papers, or occasionally with
blood spot T4 followed by TSH.
While screening in developed countries is directed at detecting

39
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

neonates with TSH elevations which are 20 mIU/l whole blood or higher,
the availability of TSH assays sensitive to 5 mlU/l permits detection of
mild elevations above normal. This permits detection of transient hyper-
thyrotopinemia. To be broadly applicable in a population, the screening
must be universal, and not omit children born in remote or impoverished
areas. For countries and regions that already have a system of universal
neonatal screening with a sensitive TSH assay in place, the data can be
examined and transient iodine deficiency recognized, usually without
further surveying.

Feasibility
Serum TSH is widely used in the field of thyroidology as a sensitive
marker for both hypothyroidism and hyperthyroidism. Methods for
determining TSH concentrations, from either dried whole blood spots
on fi lter paper or from serum, are well established and widely available.
Typically, a few drops of whole blood are collected on fi lter paper from
the cord or by prick of the heel or other site.
It is essential that sterile equipment be used, either lancets for blood
spot collection or needles and syringes for collecting whole blood from
which the serum is separated. Standard procedures for handling blood
products or objects contaminated with blood should be followed. The
risk of contracting HIV or hepatitis infection from dried blood spots is
extremely low.
Some experimental data suggest normal values for cord blood are
higher than those for heel prick blood. Blood spots, once dried, are sta-
ble. They can be stored in a plastic bag and transported even through
normal postal systems and are usually stable for up to six weeks.
It must be emphasized that the primary purpose of screening pro-
grammes is to detect congenital hypothyroidism, and its use as an indica-
tor of iodine nutrition will be a spin-off. Hence, the only additional cost
will be for data analysis. It is not recommended that a neonatal screening
programme be set up solely to assess community iodine deficiency. Less
expensive means for obtaining this information exist.
TSH screening is inappropriate for developing countries where health
budgets are low. In such countries, mortality among children under five
is high due to nutritional deficiencies and infectious diseases, and screen-
ing programmes for congenital hypothyroidism are not cost effective.

Performance
A variety of kits for measuring TSH are available commercially in devel-
oped countries. Most have been carefully standardized, and perform
adequately. Assays that utilize monoclonal antibodies, which can detect

40
4. INDICATORS OF IMPACT

TSH as low as 5 mIU/l in whole blood spots, are more useful for recog-
nizing iodine deficiency.

Interpretation
Permanent sporadic congenital hypothyroidism, with extremely elevated
neonatal TSH, occurs in approximately one of 4000 births in iodine-
sufficient countries. Other than infrequent cases of goitrogen exposure,
iodine deficiency is the only significant factor to increase this incidence.
The increase in the number of neonates with moderately elevated
TSH concentrations (above 5 mlU/l whole blood) is proportional to the
degree of iodine deficiency during pregnancy. It may be higher than
40% in severe endemic areas. When a sensitive TSH assay is used on
samples collected three to four days after birth, a <3% frequency of TSH
values >5 mlU/l indicates iodine sufficiency in a population (34).
Interpretation is complicated when antiseptics containing beta-
iodine, such as povidone iodine (Betadine™), are used for cleaning the
perineum prior to delivery or even the umbilical area of the baby. Beta-
iodine increases TSH levels in the neonate in both cord blood and heel
prick specimens.

4.4.2 Thyroglobulin (Tg)


Biological features
Tg is a thyroid protein that is a precursor in the synthesis of thyroid
hormone, and small amounts of Tg can be detected in the blood of all
healthy individuals. The thyroid hyperplasia and goitre characteristic of
iodine deficiency increases serum Tg levels, and in this setting serum
Tg reflects iodine nutrition over a period of months or years. This con-
trasts to urinary iodine concentration, which assesses more immedi-
ate iodine intake. A serum Tg assay has recently been adapted for use
on dried whole blood spots (DBS) (35,36). The assay makes sampling
practical even in remote areas. Measurement of DBS Tg in school-age
children is a sensitive indicator of iodine status in a population and can
be used to monitor improving thyroid function after iodine repletion.

Interpretation
Standard reference material for the DBS Tg assay is now available
from WHO. It is stable when stored for up to one year at temperatures
≤ -20 °C. An international reference range for DBS Tg has been estab-
lished in iodine-sufficient five to 14 year-old children that can be used for
monitoring iodine nutrition. The DBS Tg reference interval for iodine-
sufficient school-age children is 4–40 µg/l.

41
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Performance
DBS Tg correlates well with urinary iodine and thyroid size (35,36), the
other recommended indicators for monitoring iodine status in popula-
tions. It complements these tests, and can be used in conjunction with
urinary iodine to measure recent iodine intake, and thyroid volume to
assess long-term anatomic response.

Feasibility
The method is simple and robust. A drop of whole blood from a fi nger
stick (or a venipuncture sample) is spotted directly onto good-quality
fi lter paper.1 The spots are allowed to dry at room temperature (~20 °C),
and then stored in sealed low-density polyethylene bags; preferably
refrigerated at 4 °C, but they also can be stored for several weeks at cool,
dry room temperatures before analysis.

1
An example of the type of paper that can be used is Grade 903 Filter Paper produced
by Schleicher & Schuell; Einbeck, Germany.

42
Table 9 Indicators of impact at population level: summary
MONITORING AGE GROUP FOR ADVANTAGES DISADVANTAGES
INDICATOR (UNITS) ASSESSMENT
Median urinary School-age – Spot urine specimens are easy to obtain – Assesses iodine intake only over the past few days
iodine children and – The most practical biochemical marker for iodine nutrition, when – Meticulous laboratory practice is required to avoid
concentration pregnant carried out with appropriate technology and sampling contamination with iodine
(µg/l) women – Feasible to process large numbers of samples at low cost – A sufficiently large number of samples must be collected to
– Cut-off points proposed for classifying iodine nutrition into allow for varying degrees of subject hydration and other
different degrees of public health significance are well established biological variations among individuals
– External quality control program in place – Not valuable for individual assessment
Goitre rate School-age – Simple and rapid screening test – Specificity and sensitivity of palpation are low in grades 0
assessed by children – Requires no specialized equipment and 1 due to a high inter-observer variation
palpation (%) – Responds slowly to changes in iodine intake
Goitre rate School-age – A more precise measurement of thyroid volume compared with – Expensive equipment and a source of electricity is needed
assessed by children palpation – operator needs to be specially trained in the technique
ultrasound (%) – Safe, non-invasive – Responds slowly to changes in iodine intake

43
– International reference values for thyroid volume in schoolchildren
are available as a function of age, sex, and body surface area
TSH Newborns – Measures thyroid function at a vulnerable age when iodine – Not recommended to be set up solely to assess community
4. INDICATORS OF IMPACT

(mIU/l) deficiency directly affects the developing brain iodine deficiency due to expense
– If screening programs to detect congenital hypothyroidism is in – Cannot be used when antiseptics containing iodine are used
place then only additional cost will be for data analysis during delivery
– Collection by heel stick and storage on filter paper is simple – Requires use of a standardized, sensitive assay
– Blood spots can be stored for several weeks at cool, dry room – Should be taken either from the cord at delivery or by heel
temperatures prick at least 48 hours after birth to avoid physiological
newborn surge
Tg School-age – Collection by finger stick and storage on filter paper is simple – Expensive immunoassay
(µg/l) children – Can be stored for several weeks at cool, dry room temperatures, – Requires laboratory infrastructure
so sampling practical even in remote areas
– Measures improving thyroid function within several months after
iodine repletion
– Standard reference material is now available, but needs to be validated
– An international reference range has been established
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

5 Monitoring and
evaluation methods

5.1 Overview
This book has so far dealt with what should be measured, i.e. the indica-
tors of process and impact, and the technical details of their assessment.
This chapter describes how to monitor and evaluate these indicators in
the field.
This chapter includes methodologies for monitoring the process of salt
iodization at the population level to complement the discussion in Chap-
ter 3, and provides some details on monitoring methods for assessing
the impact of programs on iodine status and thyroid function. For some
monitoring activities such as performing surveys at schools or in house-
holds, both salt and impact indicators can be assessed at the same time,
thus providing a more comprehensive picture of the situation.
Attention to proper survey methodology will result in representative
results from the population. Careful attention to monitoring methods
will assure the monitoring is carried out as efficiently as possible.

5.2 Monitoring and evaluation of salt iodization programs


An IDD control programme based on salt iodization clearly cannot suc-
ceed unless all salt for human consumption is being adequately iodized.
Therefore the most important indicator to monitor is salt, and the most
important place to monitor salt is at the site of production and importa-
tion. If all salt leaving production facilities and imported salt is prop-
erly iodized, packaged, and labelled, populations consuming this salt are
likely to have their iodine requirements met.

Monitoring iodine content of salt at sites of production


Monitoring salt iodine at the production site provides an answer to
the question: “Is the salt adequately iodized, i.e. according to the level
required by the law of the country?” In view of the potential loss of
iodine further down the supply chain, this is the appropriate place where
law enforcement can take place.
Salt monitoring at the site of production is the responsibility of both

44
5. MONITORING AND EVALUATION METHODS

the salt producer (internal monitoring) as well as governmental food


inspectors (external monitoring), as discussed in Chapter 3.
The methods at the production level reflect industrial quality assur-
ance procedures. Production facilities should have a quality assurance
system that documents that their machinery is functioning correctly, and
that iodized salt leaving the facility meets government standard. Since
rapid test kits (RTK) cannot accurately measure the iodine content,
titration should be used for quality control. The exact number of sam-
ples to test and the frequency of testing will vary, but should be defined
in an operation manual with results recorded on a daily basis. A modi-
fied Lot Quality Assurance Sampling (LQAS) scheme is recommended
for implementation by producers (37).
Government food inspectors or health inspectors should carry out
periodic visits to salt production facilities to check on the in-house qual-
ity control mechanisms through record review and review of quality
assurance activities. They should also collect samples randomly from
several production batches, and have these analysed by titration at a gov-
ernment laboratory. Depending on the capacity of the food inspection
system, results should be reported monthly or quarterly.

Monitoring iodine content of salt at ports of entry


Large producers should certify that the salt they produce is iodized
within a specified range. Such producers, particularly if exporting salt,
should seek certification by the International Organization for Standard-
ization (International Standard ISO 9000 series) as an added guarantee
that their salt is adequately iodized.
Several factors affect the methods used for inspecting imported salt.
First, the lines of authority, and thus the procedures used, differ between
the food inspection system and customs control. Second, the practical
realities of border check points prevent optimal checking of salt consign-
ments entering the country.
At the actual point of entry, customs officers can realistically be expect-
ed to check documentation on large consignments of salt, and visibly
inspect all imports to check that the salt is suitably packed and labelled.
Documentation should distinguish between salt for human consumption
and industrial salt, which is not covered by iodization regulations. Ideally,
each consignment should be tested with a rapid test kit, accepting that this
is not any kind of representative sampling, and that it cannot assess actual
iodine levels. Suspect salt should be held at the border. Documentation
should distinguish between salt for human consumption and industrial
salt, which is not covered by iodization regulations.

45
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Establishing titration laboratories at points of entry for salt would


appear to be an attractive option, but is difficult to implement in prac-
tice. Unloading bags from a lorry or railway wagon to check a consign-
ment thoroughly is difficult, and only a few easily accessible bags can be
tested. Staff would have to be specially recruited and laboratories estab-
lished at considerable expense.

Monitoring salt at the wholesale and retail levels


Monitoring the iodine in salt at the retailer level provides an answer to
the question: “What is the availability of iodized salt to the consumer?”
Monitoring at this level yields a quick and easy indication of whether or
not iodized salt is available in the marketplace, and the degree to which
non-iodized salt is competing for household use. Retail-level monitoring
is not the appropriate place for law enforcement or compliance monitor-
ing, since it is difficult to confi rm the level of loss since production.
The methods used for wholesale and retail monitoring depend on the
capacity of the food inspection system, which often covers a wide range
of products entering the market. Thus, there is no prescribed sampling
method at this level, and countries have widely variable capacity and have
used many approaches. Ideally, for any given district, there are enough
market samples tested on an annual basis to determine the degree to
which non-iodized salt remains available in the marketplace, thus giving
some perspective to household coverage figures.

Monitoring salt at the household level


Monitoring the iodine in salt at the household level answers the question:
“What percentage of households uses salt iodized at any iodine concen-
tration and what percentage uses salt that is within an acceptable range
of iodine concentration?” This information indicates what is actually
used in households on a national basis and provides important informa-
tion about the successful delivery of iodized salt to the consumer as well
as about use of non-iodized salt obtained from unconventional market-
ing sources.
Coverage, and the methods used to determine it, is critical for pro-
gram monitoring. Most countries assess household use of iodized salt
through school or household surveys. These may be done by district
health staff or as part of periodic national surveys.
In order for school or household surveys to accurately represent the
populations from which the sample is taken, attention must be given to the
sampling methodology. The most common sampling methods, including
the cluster survey method, are described below, and in the appendices.
Salt from each selected household should be tested. Testing using rou-

46
5. MONITORING AND EVALUATION METHODS

tine test kits will provide an estimate of the percent of households using
salt with no iodine, but will not provide accurate information on the per-
cent using adequately iodized salt, or information on salt with excessive
iodine. Thus, titration or another quantitative method should be per-
formed on at least a sub-sample of households for any coverage survey.

5.3 Iodine status assessment


Assessing iodine status provides information on whether there is ade-
quate iodine intake in the population surveyed. Monitoring the iodine
status of a population answers the questions: “Is the salt iodization pro-
gram (or other interventions) improving iodine intake? Has iodine defi-
ciency been eliminated in this population?” Iodine status is the most
immediate measure of whether the thyroid gland has adequate iodine
to function normally and protect the individual from the manifestations
of iodine deficiency. The median urinary iodine concentration reflects
population status and is the indicator most commonly assessed.
As iodized salt use is assessed through coverage surveys which fre-
quently employ cluster sampling, assessment of iodine status usually
involves the same sampling technique. Salt coverage surveys may be con-
ducted more frequently, and are more easily ‘attached’ to other national
surveys. Iodine status assessment may be less frequent since it involves
the collection of urine, and therefore requires more fi nancial and human
resources. Follow-up urinary iodine assessments are generally performed
after intervention programs achieve a certain level of success (38).
Urinary iodine is frequently assessed through school surveys (since
this is an efficient way to estimate the household iodine nutrition situ-
ation) or through overall population assessments, as in DHS or MICS.
While the median value in a representative sample of schoolchildren or
the general population provides a reasonable population estimate, it may
not reflect the situation in pregnant women, whose iodine requirements
are greater. Sampling of pregnant women can be difficult because the
number of pregnant women present in household-based surveys may
be small. Assessing the median value in women of reproductive age or
among adolescent girls is more feasible in a population-based survey,
and may be helpful in interpreting the median population value.
Ideally, assessment of iodine status should include concurrent assess-
ment of household use of iodized salt. This provides information on both
the likely iodine intake and iodine status, making it easier to distinguish
between difficulties with iodized salt quality, and iodized salt use. When
adequately iodized salt is used, this should be reflected in adequate iodine
status in the population sampled.

47
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

5.4 Thyroid function assessment


Assessing thyroid function provides information on whether the thy-
roid gland is responding to adequate iodine intake, and is the ultimate
measure of whether a population is protected from iodine deficiency.
Assessing the thyroid status of a population answers the question: “Is
there evidence of thyroid dysfunction that may reflect inadequate iodine
intake?” Thyroid function reflects the ability of the thyroid to produce
thyroid hormone, which is essential for normal development. Thyroid
size and various measures of status such as TSH and Tg are the most
common measures of thyroid function.
The methods used for assessing thyroid function have changed with
the changing role of goitre assessment as noted in Chapter 4. In some
instances, where there is no information on whether IDD is present, or
when there is concern that IDD may be re-emerging, goitre surveys may
be useful. In such cases, the selection of schools or communities for sur-
veying should be purposive, i.e. on the basis of IDD being suspected or
predicted in that particular location. Goitre palpation of each subject
takes very little time, and the examination of a relatively large number
of children will provide a good picture of the overall IDD status in the
area sampled. Ultrasound provides a more accurate estimate of thyroid
size. Because this type of investigation is purposive, it will most likely not
be representative of any population except those in the communities or
schools assessed.
While urinary iodine is the most commonly used measure of iodine
status, the newly tested dried blood spot Tg may provide a reasonable
assessment of thyroid function in schoolchildren. Tg can be used in
household or school surveys, or through purposive sampling as described
above.

5.5 Common monitoring methods


Two approaches to monitoring iodized salt and IDD in populations
are cross-sectional surveys and sentinel surveillance. Cross-sectional
surveys are generally performed to provide representative estimates for
a population. Cross-sectional surveys can be household-based, school-
based, or clinic-based. In most cross-sectional surveys there are two
stages of selection with units selected at the fi rst stage referred to as
“clusters”. For household-based surveys, the fi rst stage is the selection of
communities or enumeration units, and the second stage is selection of
households from which individuals are assessed. For school-based sur-
veys, the fi rst stage is the selection of schools and the second stage is the
selection of students. For clinic-based surveys, the fi rst stage is the selec-
tion of clinics and the second stage is the selection of patients.

48
5. MONITORING AND EVALUATION METHODS

At the fi rst stage in cross-sectional surveys to select clusters, a fre-


quently used approach is the probability proportion to size (PPS) meth-
od. This method requires an estimate of the size at the fi rst stage of
selection. For household-based surveys this is generally based on cen-
sus data, for school-based surveys based on school enrolment, and for
clinic-based surveys based on the number of enrolled patients. Using
this method, the larger the size at the fi rst stage of selection, the
greater the likelihood of being selected as a cluster. There are a number
of advantages to PPS including the issue of not having to “weight” the
data at the analysis stage, i.e. it is a self-weighted design. The details of
PPS sampling are provided in Annex 4.
If the size of the population is not known at the fi rst stage, then either
simple random sampling (SRS) or systematic sampling can be used to
select clusters. However, if SRS or systematic sampling is used there
will be a need to “weight” the data based on the size of the cluster at the
analysis stage.
At the second stage of selection in cross-sectional surveys there is
a need to assure a random or systematic selection process. For house-
hold-based surveys this entails a method for selecting households, for
school-based surveys a method for selecting students, and for clinic-
based surveys a method for selecting patients. For school-based and
clinic-based surveys, the selection of individuals for the survey is rela-
tively straightforward in that a listing of eligible individuals is used from
which the desired number to assess are selected using SRS or system-
atic sampling. For household-based surveys, the selection of households
from a cluster may be complicated if the cluster is large in terms of the
number of households, spread out over a large geographical area, or very
unorganized. The segmentation method is frequently used in these lat-
ter situations to narrow down the area to be assessed, and is described in
more detail in Annex 4.
Cross-sectional surveys may be stratified by different geographical
areas; usually provinces or regions. Stratified surveys allow the presenta-
tion of stratum-specific estimates as well as a national estimate, but dra-
matically increase the sample size of the survey. Ideally, a minimum of
around 30 clusters are needed for each stratum. Depending on the goals
of the survey and resources available, a single 30-cluster survey may or
may not be sufficient for all countries. Some surveys may focus primarily
on the coverage and quality of iodized salt whereas some others include
measures of IDD status. Stratified surveys of iodized salt coverage can
be useful to identify geographical areas where coverage is insufficient
and lead to further enquiry concerning the causes of low coverage. In
most countries the primary prevention of IDD is through iodized salt,

49
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

and therefore knowledge of variations in IDD status by strata would pri-


marily identify variations in iodized salt coverage.
A common mistake in interpreting the results from a cluster survey
is to assume that the result from a single cluster is representative of that
area. While it is possible to look at the geographic patterns among the
clusters surveyed, it is only the overall coverage figure that is representa-
tive of the full area surveyed.
A major concern arising in school-based surveys is that children not
attending school are not represented, which may possibly lead to biased
estimates. Also, if there are feeding or vitamin-mineral supplement pro-
grammes in the schools, schoolchildren may not be a good target group
in terms of assessing IDD for the entire population. Details of school
sampling are also provided in Annex 4.
A second approach to monitoring is to collect data through sentinel
surveillance. Because cross-sectional surveys tend to be performed
infrequently and can be costly, countries should consider using this meth-
od, particularly if there is concern about the status of pregnant women.
Sentinel surveillance involves selection of a number of sites from which
routinely collected data provide results on trends. The number and loca-
tion of sites, number of individuals or samples per site, and frequency of
data collection depends on the primary purpose of the sentinel surveil-
lance and resources available. Some countries may have sentinel surveil-
lance for other conditions for which iodized salt or IDD monitoring could
be added. Sentinel sites might be based on prenatal care clinics or schools
where urinary iodine specimens are collected on a sample of pregnant
women or students. Sites may be selected in areas where IDD is known
to be prevalent or in areas with low iodized salt coverage, or they may be
selected to be reasonably representative of the country. There are three
target groups for surveillance of IDD control programmes:
1. School-age children: School-age children are a useful target group
for IDD surveillance because of their combined high vulnerability, easy
access, and applicability to a variety of surveillance activities. Affected
children can be readily examined in large numbers in school settings,
and can be assessed for urinary iodine, thyroid size, and Tg. At the
same time, other health concerns in this age group, including helminth
infections, anaemia, and behavioural factors affecting health, can be
assessed. Appropriate educational interventions can then be imple-
mented.

2. Women of childbearing age and pregnant women: Assessing


urinary iodine in women 15 to 44 years of age provides an opportu-

50
5. MONITORING AND EVALUATION METHODS

nity to establish the iodine status of a group that is particularly crucial


because of the susceptibility of the developing fetus to iodine deficien-
cy. Antenatal clinics may have high use rates, and thus a sentinel sam-
pling may provide a reasonable sample of pregnant women.

3. Neonates: Neonatal screening to identify congenital defects is well


established in many developed countries and is being introduced in
some relatively prosperous developing countries. Regular collection
of blood-spot specimens, where this is practiced, can be an important
source of information for IDD surveillance given their use in assess-
ing TSH status. This approach is recommended for monitoring IDD
control only when a screening programme is already established.

5.6 Combined micronutrient deficiency surveys


IDD prevalence surveys may be efficiently combined with those aimed
at assessing the prevalence of other micronutrient deficiencies, such as
vitamin A and iron, or other cluster surveys designed for other purposes.
The simplest way of including an IDD component is to collect urine in
order to assess urinary iodine concentration in the target group and to
ask for a household salt sample.
Benchmark national surveys such as DHS and MICS often include
information on micronutrient programs, and in some instances can be
modified to meet specific micronutrient program needs. These large
national surveys help provide periodic information, but may not be
adequate for routine monitoring of program progress.

51
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

6 Indicators of the sustainable


elimination of IDD

As programs mature, it is important to understand their vulnerability


and whether they are likely to be sustained. A number of criteria have
been established to determine whether elimination goals have been met,
and a series of programmatic indicators have been developed to help
understand the likelihood that a program will be sustained. This chapter
outlines these factors.
In considering whether the sustainable elimination of iodine deficien-
cy as a public health problem has been achieved, the following criteria
should be met (see also Table 10):

6.1 With regard to salt iodization:


• Availability and use of adequately iodized salt (>20 ppm iodine and
<40 ppm) must be guaranteed. This is demonstrated by its use by
more than 90% of households.
• Conditions demonstrating successful use of salt as vehicle for elimi-
nating IDD are:
— 95% of salt for human consumption must be iodized according to
government standards for iodine content as determined by titra-
tion, at the production or importation levels;
— The percentage of food-grade salt with iodine content of between
20 and 40 ppm in a representative sample of households must be
equal to or greater than 90% as determined by RTK and by titra-
tion in a sub-sample.

6.2 With regard to the population’s iodine status:


• The median urinary iodine concentration in the general population
should be within the range 100–199 µg/l.
• The median urinary iodine concentration in the pregnant women
population should be within the range 150–249 µg/l.
• The most recent monitoring data (national or regional) should have
been collected within the last five years.

52
6. INDICATORS OF THE SUSTAINABLE ELIMINATION OF IDD

6.3 With regard to the programmes:


1. Presence of a national multi-sector coalition responsible to the gov-
ernment for the national programme for the elimination of IDD with
the following characteristics:
• National stature;
• All concerned sectors, including the salt industry, represented,
with defi ned roles and responsibilities;
• Convenes at least twice yearly.
2. Demonstration of political commitment as reflected by:
• Inclusion of IDD in the national budget (either as specific pro-
gramme funds or through inclusion in existing programme
funds) particularly with regard to procurement and distribution
of potassium iodate (KIO3).
3. Enactment of legislation and supportive regulations on universal salt
iodization, which establishes a routine mechanism for external qual-
ity assurance.
4. Establishment of methods for assessment of progress in the elimina-
tion of IDD as reflected by:
• Reporting on national programme progress every three years.
5. Access to laboratories as defi ned by:
• Laboratories able to provide accurate data on salt and urinary
iodine levels and thyroid function.
6. Establishment of a programme of education and social mobilization
as defi ned by:
• Inclusion of information on the importance of iodine and the use
of iodized salt, within educational curricula.
7. Routine availability of data on salt iodine content as defi ned by:
• Availability at the factory level at least monthly, and at the house-
hold level at least every five years.
8. Routine availability of population-based data on urinary iodine eve-
ry five years.
9. Demonstration of ongoing cooperation from the salt industry as
reflected by:
• Maintenance of quality control measures and absorption of the
cost of iodate/iodide.
10. Presence of a national database for recording of results of regular
monitoring procedures which include population-based household
coverage and urinary iodine (with other indicators of iodine status
and thyroid function included as available).

53
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Table 10 Summary of criteria for monitoring progress towards sustainable


elimination of IDD as a public health problem
INDICATORS GOALS

Salt iodization
Proportion of households using
adequately iodized salt >90%
Urinary iodine
Median in the general population 100–199 µg/l
Median in pregnant women 150–249 µg/l
Programmatic indicators Attainment of eight out of 10 indicators specified in
Section 6.3

6.4 Programme evaluation


There is a need for periodic review of the entire programme, with the
help of WHO, UNICEF, ICCIDD, and other appropriate organizations
involved in IDD elimination. Such external evaluation provides inde-
pendent assessment, which is extremely helpful to a country programme.
It can also provide programmes with reassurance of their performance
and effectiveness.
For acknowledgement of attainment of the sustainable elimination of
IDD, countries may request an evaluation through UNICEF, WHO,
or ICCIDD country offices. Details for this process are provided in
Annex 6.

54
Annexes
ANNEX 1

Titration method for determining


salt iodate and salt iodide content

A1.1 Titration method for determining salt iodate content


The iodine content of iodated salt samples is measured using the iodo-
metric titration method (16,23,37). The method consists of preparing
the reagent solutions, which may last for variable periods of time, and
then using these reagents in the titration procedure.
Usually, salt samples of 10 g each are dissolved in a measured amount
of water for the titration analysis. However, in the case of coarse salt and
in salt containing impurities, a bigger sample weight of 50 g salt will
yield more accurate results. A chemical analyst will be able to advise
on the appropriate glassware, preparation of reagents (including adjust-
ments to the concentrations of some of the reagents), and the necessary
calculations to obtain the correct results.
For community or population surveys, 10 g salt samples are sufficient;
however, for monitoring the iodine content at the production level, 50 g
salt samples are preferred for the titration procedure.

A1.1.1 Description of the reaction


The reaction mechanism includes two steps:
• Liberation of free iodine from salt: The addition of H2SO4 liber-
ates free iodine from the iodate in the salt sample. Excess potassium
iodide (KI) is added to help solubilise the free iodine, which is quite
insoluble in pure water under normal conditions.
• Titration of free iodine with thiosulfate: free iodine is consumed
by sodium thiosulfate in the titration step. The amount of thiosulfate
used is proportional to the amount of free iodine liberated from the
salt. Starch is added as an external (indirect) indicator of this reac-
tion and reacts with free iodine to produce a blue colour. When added
towards the end of titration (i.e. when only a trace amount of free
iodine is left) the loss of blue colour, or end-point, which occurs with
further titration, indicates that all remaining free iodine has been con-
sumed by thiosulfate.

57
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Reaction steps for iodometric titration of iodate


1. IO3 + 5l– + 6H + → 3I2+ 3H2O
(from salt) (from Kl) (from H2SO4)
2. 2Na2S2O3 + I2 → 2NaI + Na2S4O6
Sodium thiosulfate Iodine Sodium iodide Sodium tetrathionate

A1.1.2 Reagent preparation


The preferred water for this method should be double-distilled or
deionized water, which requires provision of a distillation unit. As a simpler
alternative, regular tap water treated with a mixed bed deionizing resin can
be used, thus avoiding the need for an expensive distillation unit. Many
reputable chemical and pharmaceutical companies supply deionized,
double-distilled, and purified water which is iodine-free.
• 0.005 N Sodium thiosulfate (Na2S2O3): Dissolve 1.24 g
Na2S2O35H 2O in 1000 ml water. Store in a cool, dark place. This vol-
ume is sufficient for 100 to 200 samples, depending on their iodine
content. The solution is stable for at least one month, if stored proper-
ly. Standardization of sodium thiosulfate with a volumetric solution of
potassium iodate is recommended. The concentration of the sodium
thiosulfate could be adjusted to accommodate the analysis of larger
sample weights (e.g. 50 g or 100 g salt samples).
• 2 N Sulfuric acid (H2SO4 ): Slowly add 6 ml concentrated H 2SO4
to 90 ml water. Make to 100 ml with water. This volume is sufficient
for 100 samples. The solution is stable indefi nitely. Always add acid to
water, not water to acid, to avoid excess heat formation and spitting of
acid. Stir solution while adding acid.
• 10% Potassium iodide (KI): Dissolve 100 g KI in 1000 ml water.
Protect reagent from direct light. Store in a brown bottle in a cool,
dark place. Properly stored, the solution is stable for six months, pro-
vided no change occurs in the colour of the solution. This volume is
sufficient for 200 samples.
• Starch indicator solution: Dissolve approximately 15-30 g of rea-
gent-grade sodium chloride (NaCl) in 100 ml water. While stirring,
add NaCl until no more dissolves. Heat the contents of the beaker until
excess salt dissolves. While cooling, the NaCl crystals will form on the
sides of the beaker. When it is completely cooled, decant the super-
natant into a clean bottle. This solution is stable for six to 12 months.
Suspend 1 g chemical starch in 10 ml water at room temperature, then
continue to boil until it completely dissolves. Add the saturated NaCl

58
ANNEX 1. TITRATION METHOD FOR DETERMINING SALT IODATE AND SALT IODIDE CONTENT

solution to make 100 ml starch solution. This volume is sufficient


for testing 20 to 45 samples. Preferably, prepare fresh starch solution
every day since this solution deteriorates easily, although it is stable for
up to one month.

A1.1.3 Procedure
Sampling of salt
Prior to taking a 10 g or 50 g salt sample for analysis, salt should be
thoroughly mixed, preferably in zip-lock bags or appropriate contain-
ers to ensure that the iodine is homogeneously distributed in the salt.
Usually 10 g iodated salt is dissolved in 50 ml distilled water. Optional:
50 g iodated salt could be thoroughly dissolved in 250 ml distilled water,
from which an aliquot of 50 ml could be analysed as mentioned in the
titration step below, without adjusting the concentrations of the reagents
or calculation.

Titration step
Once the salt is dissolved in the measured amount of water, sulfuric acid
(1–2 ml) and potassium iodide (5 ml) is added to the salt solution, which
in the presence of iodine will turn yellow. The reaction mixture is then
kept in a dark place (with no exposure to light) for five to 10 minutes to
reach the optimal reaction time, before titrated with sodium thiosulfate
using starch (2 ml) as the indirect indicator. The concentration of iodine
in salt is calculated based on the titrated volume (burette reading) of
sodium thiosulfate according to the formula mentioned below, or alter-
natively it could be read off a pre-calculated table for the specific method
(e.g. method: 10 g salt titrated with 0.005N sodium thiosulfate).

Calculation
mg/kg (ppm) iodine = titration volume in ml x 21.15 x normality
of sodium thiosulfate x 1000 / salt sample weight in g
Special note: 0.005 N sodium thiosulfate consumes 0.1058 mg iodine/ml.

Precaution
The 10% potassium iodide reagent stock needs to be protected from
direct light, and the reaction mixture (after the addition of sulfuric acid
and potassium iodide) should be kept in the dark before titration to pre-
vent a side reaction which may occur when these solutions are exposed
to light, causing iodide ions to be oxidized to iodine.

59
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

A1.2 Titration method for determining salt iodide content


While the use of potassium iodide (KI) is not common for salt fortifica-
tion in many developing countries, basic details of a titration method
(23) suitable for analysing salt iodized with KI are provided here.

A1.2.1 Description of the reactions


In the iodometric titration for salt fortified with potassium iodide:
• Liberation of iodine: Bromine water oxidizes iodide ions to free
iodine. Sodium sulfite and phenol are added to destroy excess bro-
mine so that no further oxidation of iodine can occur before KI solu-
tion is added.
• Titration: The titration reaction with thiosulfate is the same as that
described in the iodometric titration method for iodated salt men-
tioned earlier.

A1.2.2 Reagent preparation


Reagents for oxidization of iodide to free iodine:
• Methyl orange indicator (C14H14N3NaO3S): Dissolve 0.01 g
methyl orange in 100 ml water.
• Bromine water (Br2ag): Place required volume (e.g. 5–50 ml)
in a small flask (keep in fume hood due to dangerous fumes and
wear appropriate personal protective clothing, e.g. masks, gloves and
goggles). Safety precaution in case of spills: neutralize bromine water
of its halogen component by sprinkling sodium metabisulfite, sodium
sulfite or even domestic baking soda (bicarbonate of soda).
Preparation of bromine water from liquid bromine (Br2 ): Decant the
vapours from the liquid bromine in 50 ml distilled water into a 100
ml wide mouth glass bottle with a screw cap or stopper. Cap the
bottle when the airspace above water is fi lled with red vapours. Swirl
the bottle containing the water in order to mix the contents. As the
bromine dissolves, the solution will become yellow in colour. The
process above should be repeated at least once more. Typically
bromine water should be orange in colour.
• Sodium sulfite solution (Na2SO3): Dissolve 1 g sodium sulfite in
l00 ml water. Prepare fresh sodium sulfite solution regularly, since the
solution deteriorates easily.
• Phenol solution (C6H6O): Dissolve 5 g phenol in 100 ml water.
All reagents prepared and used in the iodate method are also applicable
to the iodide method for the titration step.

60
ANNEX 1. TITRATION METHOD FOR DETERMINING SALT IODATE AND SALT IODIDE CONTENT

A1.2.3 Procedure
Sampling
As described in the iodate method.

Oxidation step (iodide method)


Once the salt (10 g) is dissolved in the measured amount of water (50
ml), a few drops of methyl orange indicator are added, followed by a few
drops of sulfuric acid until the orange colour turns to pink, resulting in
the neutralization of the reaction mixture. With the addition of bromine
water (0.5 ml-5.0 ml, depending on the level of salt iodization), the reac-
tion mixture changes to yellow. To consume the excess bromine, the
reaction mixture is titrated with sodium sulfite until the solution turns
to pale yellow, followed by the washing down of the sides of the flask
with small amounts of water, and the addition of three drops of phenol,
resulting in a clear reaction mixture.

Titration step (iodide & iodate method)


Follow the same titration steps and calculations as described in the iodate
method.

61
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

ANNEX 2

Method for determining thyroid size


by ultrasonography

Thyroid gland size can be measured in the field by ultrasonography. In


choosing an echocamera for this purpose, durability, reliability, good
screen quality, sharp focus, and an easy-to-use marking system should
be emphasized. The machine should be equipped with a high resolution,
real-time, 4 to 6 cm linear, 7.5–10 MHz transducer.

A2.1 Location and anatomy of the thyroid gland (Figure 3)


• Superficial, butterfly-shaped gland in lower, anterior portion of neck.
• Right and left lobes are connected at midline by isthmus.
• Lateral borders: common carotid artery and internal jugular vein.
• Medial border: trachea.
• Anterior borders: sternocleidomastoid, sternothyroid, and sternohy-
oid muscles.
• The normal thyroid is variable in size. At age 6 to 12 years, its approx-
imate weight is 15–25 g.

Figure 3 Anatomic description of the thyroid gland

Trachea

Thyroid gland

L
D

Width (W): medial – lateral dimension


Depth (D): anterior – posterior dimension
Length (L): cranial – caudal dimension

62
ANNEX 2. METHOD FOR DETERMINING THYROID SIZE BY ULTRASONOGRAPHY

A2.2 Sonographic appearance


• The normal thyroid is mid-gray with medium-level echoes and an
even, homogeneous texture.
• Lobes appear more echogenic or hyperechoic to adjacent muscles.
• Branches of intrathyroid arteries and veins may appear as 0.5–1.0 mm
anechoic tubular, linear structures, but they are rarely delineated.
• The capsule of the thyroid surrounds the gland and appears as a thin
line hyperechoic to the gland parenchyma.
• In diffuse goitre, the gland is enlarged and its echogenicity is slightly
enhanced.

A2.3 Scanning protocol


A2.3.1 Subject position
• Children can be measured supine with a pillow or rolled towel under
the shoulders to maintain neck extension. Alternatively, they can be
seated upright in a hard-backed chair with their back and shoulders
straight, neck mildly hyperextended, and head turned slightly away
from side of interest.
• The standing position is generally not recommended because of insta-
bility.

A2.3.2 Transducer
• Water-soluble gel is used.
• Transducer held at a 90-degree angle to skin, using only minimal
pressure so as not to distort the gland anatomy.

A2.3.3 Transverse Study (Figure 4)


• Best done on a split screen, visualizing both lobes per screen.
• The trachea with its echogenic cartilage rings and air shadows appears
in the midline; the echo-free lumina of the carotid arteries (pulsa-
tion) and jugular veins (distension on Valsalva) delineate the lateral
aspect.
• Begin with the transducer perpendicular in the transverse plane above
the sternal notch; move the transducer superiorly to view the entire
gland from inferior to superior aspect; return to image which shows
the lobe at its greatest depth and width; and freeze the image.
• Change to other side of the screen, repeat scan on opposite lobe, and
freeze.
• Measure the maximal width (mediolateral) and depth (anteroposteri-
or) of the transverse section of each lobe, with the depth measurement
at a 90-degree angle to the skin surface and the width measurement at
90 degrees to the depth measurement.

63
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Figure 4 Transverse scan

Width

Depth

• The measurement should not include the thyroid capsule (hyperecho-


ic to the gland tissue) or the thyroid isthmus.
• Note that the carotid, particularly in a subject with an enlarged thy-
roid, may indent the posterolateral aspect of the gland.

A2.4 Longitudinal Study (Figure 5)


• One thyroid lobe is measured per screen. The strap muscles appear
anteriorly as hypoechoic structures relative to the thyroid. Posterior
to the medial portion of the thyroid, the trachea with its echogenic
cartilage and air shadows is often seen. Posterior to the lateral portion
of the thyroid, venous structures and the common carotid appear as
echo-free tubular structures.
• Begin with the transducer perpendicular in the sagittal plane above
the sternal notch, move the transducer superiorly to view the entire
gland from inferior to superior and medial to lateral aspect, return to

Figure 5 Longitudinal scan

Length

64
ANNEX 2. METHOD FOR DETERMINING THYROID SIZE BY ULTRASONOGRAPHY

image which shows the lobe at its greatest length (craniocaudal), and
freeze.
• To obtain the greatest length, because of the inferior convergence of
the lobes, the transducer is often oriented with its superior end slightly
diverging from the midline. Measure the maximal length of the longi-
tudinal section of the lobe.
• Repeat scan on opposite lobe and again measure the maximal length
of the longitudinal section.
• If the length of the gland exceeds the length of the transducer, the
longitudinal measurement is done by splitting the lobe length in two
scans, measuring to an internal (preferable) or external landmark,
and summing the measurements to obtain the length.

A2.5 Calculation of thyroid volume and body surface area


The volume of the lobe is calculated from the measurements of the depth
(d), the width (w), and the length (l) of each lobe by the formula:
V (ml) = 0.479 x d x w x 1 (cm)
The thyroid volume is the sum of the volumes of both lobes. The volume
of the isthmus is not included.
Thyroid volume can be easily calculated using a calculator or personal
computer during data entry. Portable ultrasound equipment is relatively
rugged, but requires electricity. However, it can be operated from a car
battery with the aid of a transformer. Trained operators can perform up
to 100 or more examinations per day.
The body surface area is calculated using the formula of Dubois and
Dubois (39):
BSA (m 2) = W0.425 x H0.725 x 71.84 x 10 -4
It should be emphasized that by using the ultrasonography criteria, a
thyroid gland will be called goitrous when its values will be above the
97th percentile of the volume found in an iodine-replete population used
as control. Reference values for the 97th percentile for thyroid volume,
as a function of both age and body surface area (BSA), are available
(33). In areas with a high prevalence of protein-energy malnutrition, the
BSA reference is recommended.

65
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

ANNEX 3

Method for measuring urinary


iodine using ammonium persulfate
(method A)
A3.1 Principle
Urine is digested with ammonium persulfate. Iodide is the catalyst in
the reduction of ceric ammonium sulfate (yellow) to the cerous form
(colourless), and is detected by the rate of colour disappearance (Sand-
ell-Kolthoff reaction).

A3.2 Equipment
Heating block with a temperature range up to 110°C or above (ven-
ted fume hood recommended, but not essential); spectrophotometer;
thermometer, test tubes (13 x 100 mm); assorted glassware and storage
bottles; pipettes; vortex; magnetic hotplate; magnetic stirrer; analytical
balance or top loader scales with a readability of at least 0.001 g and a
capacity of approximately 250 g.

A3.3 Reagents
1. Ammonium persulfate (H8N2O8S2)
2. Arsenic trioxide (As2O3)
3. Sodium chloride (NaCl)
4. Sulfuric acid (H2SO4)
5. Sodium hydroxide (NaOH)
6. Cerric ammonium sulfate [Ce(NH4)4(SO4)4 ·2H 2O]
7. Deionized water (H2O)
8. Potassium iodate (KIO3)
Use analytical grade chemicals for the preparation of all solutions

A3.4 Solutions
Ammonium persulfate (1.0 mol/l): Dissolve 114.1 g ammonium
persulfate in 500 ml deionized water. Store in darkness; stable for one
month. Keep refrigerated to prevent decomposition.
5 N Sulfuric acid: Slowly add 140 ml concentrated (36 N) sulfuric acid
to about 700 ml deionized water (careful – this generates heat!). When
cool, adjust with deionized water to a fi nal volume of 1 litre.

66
ANNEX 3. METHOD FOR MEASURING URINARY IODINE USING AMMONIUM PERSULFATE (METHOD A)

3.5 N Sulfuric acid: Slowly add 97 ml concentrated (36 N) sulfuric


acid to about 700 ml deionized water (careful – this generates heat!).
When cool, adjust with deionized water to a fi nal volume of 1 litre.
Sodium hydroxide (0.875 mol/l): Dissolve 17.5 g sodium hydroxide
pellets in 500 ml deionized water.
Arsenious acid solution (0.025 mol/l): Place 5 g arsenic trioxide and
25 g sodium chloride in a 1-L Erlenmeyer flask, then slowly add 200 ml
of 5 N sulfuric acid, heat gently while stirring to dissolve, and then cool
to room temperature. Dilute with deionized water to 1 litre. Store in
darkness; stable for months.
Alternative Arsenious acid solution (0.05 mol/l): Dissolve 10 g
arsenic trioxide in 200 ml of 0.875 mol/l sodium hydroxide solution. Slow-
ly add 32 ml of concentrated (36 N) sulfuric acid to the solution in an ice
bath while stirring. After cooling, add 25 g of sodium chloride and then
adjust to 1 litre with cold deionized water with stirring to dissolve. Store in
darkness, stable for months. This solution is recommended for the micro-
titer plate application as well as for manual spectrophotometric analysis.
Ceric ammonium sulfate solution (0.038 mol/l): Dissolve 24 g ceric
ammonium sulfate in 1 litre 3.5 N H 2SO4. Make up at least 24 h before
use, and store in darkness; stable for months.
Standard iodine solution (KIO3):
Stock standard A: Dissolve 0.840 g potassium iodate in deionized water
to a fi nal volume of 500 ml in a volumetric flask. This solution is equiva-
lent to 1000 µg/ml.
Stock standard B: Dilute 5 ml of standard A in deionized water to a fi nal
volume of 500 ml in a volumetric flask. This solution is equivalent to
10 µg/ml. Store all stock standards in white or brown plastic bottles, in a
refrigerator away from light. The solution is stable for 6-12 months.
Working standards: Prepare by adding aliquots of 200, 400, 800, 1200,
2000, and 3000 µl of standard B, each diluted with water to a fi nal
volume of 100 ml in volumetric flasks. These standards are equivalent
to iodine concentrations of 20, 40, 80, 120, 200, and 300 µg/l. Include a
zero standard (deionized water). Store in plastic bottles in a refrigerator
away from light. Stable for 1-3 months.
Note: 1.68 mg KIO3 contains 1.0 mg iodine. 1000 µg iodine/l is equiva-
lent to 7.9 µmol/l.

A3.5 Procedure
1. Allow urine to reach room temperature, then mix urine to suspend
sediment.

67
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

2. Pipette 250 µl of each urine sample, working standards ranging from


0 to 300 µg/l and internal urine controls, into 13 x 100 mm test tubes.
Duplicate iodine standards and a set of internal urine controls should be
included in batch.
3. Add 1 ml ammonium persulfate to each tube.
4. Heat all tubes for 60 minutes at 91-95 °C.
5. Cool tubes to room temperature.
6. Add 2.5 ml arsenious acid solution. Mix by inversion or vortex. Let
stand for 15 minutes.
7. Add 300 µl of ceric ammonium sulfate solution to each tube at 15
to 30-second intervals between successive tubes, mixing each with
a vortex after addition. A stopwatch should be used for this. With
practice, a 15-second interval is convenient.
8. Allow to sit at room temperature. Exactly 30 minutes after the addi-
tion of ceric ammonium sulfate to the fi rst tube, read its absorbance
at 405 or 420 nm. Read successive tubes at the same time intervals as
when adding the ceric ammonium sulfate.

A3.6 Calculation of results


Construct a standard curve on graph paper by plotting the iodine con-
centration of each standard on the abscissa against its optical density
at 405 nm (OD405) on the ordinate. Alternatively, a standard curve
can be constructed by plotting the log of the absorbance at 405 nm
on the X-axis versus the standard iodine concentration in µg/l on the
Y-axis with a scatter plot, using Exel on a desktop computer. The iodine
concentration in µg/l of each specimen is calculated by using the equa-
tion of the linear trendline of this chart. As this is an inverse endpoint
colour reaction, all specimens that have absorbance values lower than the
acceptable standard curve (or calculate concentration >300 µg/l) should
be diluted, preferably 1:3 or 1:5 dilutions, or as required, with water and
re-essayed. The most common absorbancies observed using this meth-
od range between 0.300 and 1.800 for standards with concentrations
between 300 µg/l and 0 µg/l.

A3.7 Notes
1. This is modified from the former method (method B, see page 30),
substituting ammonium persulfate for chloric acid (more toxic) as the
digestant (26, 27, 40).
2. Since the digestion procedure has no specific end-point, it is essential
to run blanks and standards with each assay to allow for variations in
heating time, etc.

68
ANNEX 3. METHOD FOR MEASURING URINARY IODINE USING AMMONIUM PERSULFATE (METHOD A)

3. The exact temperature, heating time, and cooling time may vary.
However, within each assay, the interval between the time of addition
of ceric ammonium sulfate and the time of the reading must be the
same for all samples, standards, and blanks.
4. With the longer ceric ammonium sulfate incubation and with 15-
second interval additions of ceric ammonium sulfate, up to 120 tubes
can be read in a single assay.
5. The volumes and proportions of samples and reagents can be varied
to achieve different concentrations or a different curve shape, if con-
ditions warrant. If different tube sizes are used, corresponding sized
holes in the heating block are also needed.
6. If necessary, this method could probably be applied without a heating
block, using a water, oil, or sand bath, but this is not recommended.
It is essential that all tubes be uniformly heated and that the tempera-
ture be constant within the range described above.
7. Test tubes can be reused if they are carefully washed to eliminate any
iodine contamination. Durable 13 x 100 mm or 16 x 100 mm culture
tubes with screw caps are recommended (e.g., Corning or KIMAX
tubes).
8. This method can be slighty modified to be suitable for automation,
which allows for colorimetric readings to be done in microtiter plates
and subsequently with a scanner. For example, with the same diges-
tion step, only the ceric ammonium sulfate concentration could be
adjusted to approximately 0.016 or 0.019 mol/l to accomodate the
microtiter plate applications (30).
9. The Centers for Disease Control and Prevention (CDC), Atlanta,
USA provides urinary iodine laboratories the opportunity to partici-
pate in an external quality control program (EQUIP).

69
ANNEX 4

Methodology for selection of survey


sites by PPS sampling1

Since it is usually not possible to randomly select households, a stratified


method for household selection is used for population-based surveys.
Such “cluster” surveys require identification of a sampling unit such as a
village or ward as the “cluster” or site from which households are select-
ed. In the selection of survey sites (or clusters), the basic goal is to select
sites that will be representative of the area to be surveyed. Methods used
for performing household-based and school-based surveys are described
in this annex.

A4.1 Household-based surveys


For a standard, population-based “cluster” survey, the fi rst step is to obtain
the “best available” census data for all of the communities in the area of
interest. This information is usually available from the central statistical
office within the ministry that performs the census for the country.
From the census data, select the data for the area chosen for the sur-
vey. Make a list with four columns (see Table 11). The fi rst column lists
the name of each community. The second column contains the total
population of each community. The third column contains the cumula-
tive population – this is obtained by adding the population of each com-
munity to the combined population of all of the communities preceding
it on the list. The list can be in any order: alphabetical; from smallest to
largest population; or geographical.
The sampling interval (k) for the survey is obtained by dividing the
total population size by the number of clusters to be surveyed. A random
number (x) between 1 and the sampling interval (k) is chosen as the
starting point using random number tables, and the sampling interval
is added cumulatively. The communities to be surveyed are those with
the (x+n)th person, the (x+2n)th, (x+3n)th, person and so on up to the
(x+30n)th person.
The 30 clusters should be plotted on a map. Next, a logical sequence
for the fieldwork should be developed for each of the survey teams.

1
Adapted from: Sullivan KM et al. (40)

70
ANNEX 4. METHODOLOGY FOR SELECTION OF SURVEY SITES BY PPS SAMPLING

A4.1.1 An example of selecting communities in a cluster survey


In the fictitious area of El Saba, there are 50 communities (Table 11).
In practice there would usually be many more than 50 communities, but
this number is used for illustrative purposes to describe the method.
In Table 11 on the opposite page, the fi rst column contains the names
of the communities, the second column the population of each commu-
nity, and the third column the cumulative population. A fourth column
is used for identifying which communities will have one or more clusters
selected.
Follow four steps to select communities to be included in the survey:
1. Calculate the sampling interval by dividing the total population by the
number of clusters. In this example, 24 940 / 30 = 831.
2. Choose a random starting point (x) between 1 and the sampling inter-
val (k, in this example, 831) by using the random number table. For
this example, the number 710 is randomly selected.
3. The fi rst cluster will be where the 710th individual is found, based on
the cumulative population column, in this example, Mina.
4. Continue to assign clusters by adding 831 cumulatively. For example,
the second cluster will be in the village where the value 1541 is located
(710 + 831 = 1541), which is Bolama. The third cluster is where the
value 2372 is located (1541 + 831 = 2372), and so on. In communi-
ties with large populations, more than one cluster will probably be
selected.
If two clusters are selected in one community, when the survey is per-
formed the survey team would divide the city into two sections of
approximately equal population size and perform a survey in each sec-
tion. Similarly, if three or more clusters are in a community, the commu-
nity would be divided into three or more sections of approximately equal
population size.

A4.1.2 Selecting households within clusters


Within each cluster there is a need to select households for the assess-
ment. As a general rule, we recommend that, through appropriate sample
size calculations, the same number of households be visited in each clus-
ter. In most instances, a sample size between 600 and 900 is sufficient
to have a reasonable confidence interval around the coverage estimate.
Thus, for example, a 30-cluster survey is desired, and based on sample
size calculations, it is found that 20 households are to be visited in each
cluster. There are several methods for selecting households within a clus-
ter. In some settings the national census organization may have maps of
the areas and census personnel can randomly select the households to

71
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Table 11 Selection of communities in El Saba using the PPS method


NAME POPULATION CUMULATIVE CLUSTER NAME POPULATION CUMULATIVE CLUSTER
POPULATION POPULATION

Utural 600 600 Ban Vinai 400 10 800 13


Mina 700 1 300 1 Puratna 220 11 100
Bolama 350 1 650 2 Kegalni 140 11 240
Taluma 680 2 380 3 Hamali-Ura 80 11 320
War-Yali 430 2 810 Kameni 410 11 730 14
Galey 220 3 030 Kiroya 280 12 010
Tarum 40 3 70 Yanwela 330 12 340
Hamtato 150 3 220 4 Bagvi 440 12 780 15
Nayjaff 90 3 310 Atota 320 13 100
Nuviya 300 3 610 Kogouva 120 13 220 16
Cattical 430 4 040 5 Ahekpa 60 13 280
Paralai 150 4 190 Yondot 320 13 600
Egala-Kuru 380 4 570 Nozop 1 780 15 380 17
18
Uwarnapol 310 4 880 6 Mapazko 390 15 770 19
Hilandia 2 000 6 880 7
8 Lotohah 1 500 17 270 20
Assosa 750 7 630 9 Voattigan 960 18 230 21
22
Dimma 250 7 880 Plitok 420 18 650
Aisha 420 8 300 10 Dopoltan 270 18 900
Nam Yao 180 8 480 Cococopa 3 500 22 400 23
24
25
26
27
Mai Jarim 300 8 780 Famegzi 400 22 820
Pua 100 8 880 Jigpelay 210 22 840
Gambela 710 9 590 11 Mewoah 50 22 890
Fugnido 190 9 880 12 Odigla 350 23 240 28
Degeh Bur 150 10 030 Sanbati 1 440 24 680 29
Mezan 450 10 480 Andidwa 260 24 940 30

72
ANNEX 4. METHODOLOGY FOR SELECTION OF SURVEY SITES BY PPS SAMPLING

be sampled, and provide detailed maps to enumeration teams. In other


situations, detailed maps may not be available at the national level and
the teams may need to initially spend time at each cluster to perform the
household selection themselves. One approach to household selection is
to carefully map all households within the cluster and then either ran-
domly or systematically select households to survey. While this approach
is ideal, it often requires an additional visit to the cluster, and this can
add significantly to the survey cost. Another approach, frequently used
in EPI surveys in the past, is to randomly select one household within the
cluster and then select subsequent households using the “next nearest
household” approach, or selecting households in a specified direction.
We do not recommend these approaches, as they may allow some bias in
household selection. An alternative recommended method is a segment
method. On arrival in the cluster, if the cluster is large, visually divide
the cluster into segments. With segmentation, there is an attempt to
divide the cluster into approximately equal sample size segments based
on roads, rivers, or other geographic demarcations. Each segment should
have approximately the same number of households. Once divided, one
segment is randomly selected, and a random or systematic selection of
households is sampled within that segment.

A4.1.3 Selecting individuals within households


Once households are selected, the response can be taken from the head
of the household since the type of salt used in the household likely affects
all household members. It is useful to consider collection of urine speci-
mens for urinary iodine assessment in school-age children and pregnant
and lactating women, as this will help understand overall iodine intake
in these vulnerable groups.
The considerations noted above apply to estimating the proportion
of households using iodized salt. Further sample size calculations are
needed if additional information is collected, such as urinary iodine or
vitamin A supplementation, and this may affect both the number of
households to be sampled, and the selection of individuals within the
household.

A4.2 School-based surveys


If a school-based survey is to be performed, the Ministry of Education
should be contacted to obtain a listing of all schools with children of the
appropriate age for the survey. Because the age range for the survey is 6
to 12 years, the grades in which these children are likely to be enrolled
should be determined. Ideally, the Ministry of Education will have such
a listing.

73
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

If one nationwide survey is performed, a listing of schools for the


entire nation is needed. If subnational estimates are required, then a
listing of the schools for each subnational area is needed. If enrolment
information for each school is available, the PPS method should be used
for selection. If enrolment information is not available, then systematic
sampling can be performed.

A4.2.1 Selecting schools


When performing school-based surveys in a geographical area, the fi rst
questions are:
• Is there a list of all schools in the geographic area with the appropriate
age range?
• If there is a list of schools, is the number of pupils in each school
known?
In most areas, a list of schools and their respective enrolments is availa-
ble. Ensure that there is the same number of grades/levels in the schools.
If a list of schools and enrolments is available, the selection of schools
should be performed using the PPS method described for selecting com-
munities. If there is a list of schools but the enrolments are not known,
schools can be selected using systematic selection.
Using systematic selection, rather than PPS, complicates analysis
somewhat. However, if enrolment information cannot be obtained eas-
ily there may be no alternative. If there is an extremely large number of
schools in an area, or if a listing of all schools does not exist, another
method can be used. This alternative method is described later in these
guidelines.

Method 1 – schools when their enrolments are known


In this situation the PPS method for selecting communities, as described
earlier in this chapter, should be used. First, generate a list of schools
similar to that shown in Table 12. Second, determine the cumulative enrol-
ment. Finally, select schools using the same PPS method as described for
selecting communities (see Table 11).

Table 12 Selection of schools using the PPS method


SCHOOL ENROLMENT CUMULATIVE ENROLMENT

Utural 600 600


Mina 700 1300
Bolama 350 1650
Etc.

74
ANNEX 4. METHODOLOGY FOR SELECTION OF SURVEY SITES BY PPS SAMPLING

Method 2 – a list of schools is available, but enrolments are not known


When a list of schools is available but the enrolment of each school is not
known, the systematic selection method should be employed as follows.
• Obtain a list of the schools and number them from 1 to N (the total
number of schools).
• Determine the number of schools to sample (n), usually 30.
• Calculate the “sampling interval” (k) by N/n (always round down to
the nearest whole integer).
• Using a random number table, select a number between 1 and k. Use
the randomly selected number to refer to the school list, and include
that school in the survey.
• Select every kth school after the fi rst selected school.

Example of systematic selection of schools


For illustrative purposes, Table 13 lists 50 schools. The following meth-
od would be used to select eight schools:
Step one: There are 50 schools, therefore N = 50.
Step two: The number of schools to sample is eight; therefore n = 8.
Step three: The sampling interval is 50 / 8 = 6.25; round down to the
nearest whole integer, which is 6; therefore, k = 6.
Step four: Using a random number table, select a number from 1 to
(and including) 6. In this example, suppose the number
selected had been 3. Accordingly, the fi rst school to be
selected would be the third school on the list, which in this
example is Bolama.
Step five: Select every sixth school thereafter; in this example, the
selected schools would be the 3rd, 9th, 15th, 21st, 27th,
33rd, 39th, and 45th schools on the list.
In some circumstances, this method might result in the selection of more
than the number needed. In the above example, for instance, had the
random number chosen in step four been 1 or 2, then nine schools would
have been selected rather than eight. This is because the value for k was
rounded down from 6.25 to 6.
In this situation, to remove one school so that only eight are selected,
again go to the random number table to pick a number. The school that
corresponds to that random number is removed from the survey.
To analyse properly the data collected using systematic sampling, addi-
tional information needed would include the number of eligible pupils in
each school. Note that usually 30 clusters are selected; the eight indicated
in Table 13 have been selected in this example for illustrative purposes
only.

75
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Table 13 Selection of schools using the systematic selection method


SCHOOL SELECTED SCHOOL SELECTED

1 Utural 26 Ban Vinai


2 Mina 27 Puratna Y
3 Bolama Y 28 Kegalni
4 Taluma 29 Hamali-Ura
5 War-Yali 30 Kameni
6 Galey 31 Kiroya
7 Tarum 32 Yanwela
8 Hamtato 33 Bagvi Y
9 Nayjaff Y 34 Atota
10 Nuviya 35 Kogouva
11 Cattical 36 Ahekpa
12 Paralai 37 Yondot
13 Egala-Kuru 38 Nozop
14 Uwarnapol 39 Mapazko Y
15 Hilandia Y 40 Lotohah
16 Assosa 41 Voattigan
17 Dimma 42 Plitok
18 Aisha 43 Dopoltan
19 Nam Yao 44 Cococopa
20 Mai Jarim 45 Famegzi Y
21 Pua Y 46 Jigpelay
22 Gambela 47 Mewoah
23 Fungido 48 Odigla
24 Degeh Bur 49 Sanbati
25 Mezan 50 Andidwa

Method 3 – an extremely large number of schools


In very large populations, it may not be possible or efficient to select
schools using either the PPS or the systematic selection method. For
example, Szechwan Province in China has a population of approximate-
ly 100 million. Even if a list of schools were available at the provincial
level, it would take much time and effort to select schools using either of
these methods.
Accordingly, another approach may be more appropriate. First, select
districts using the PPS method. Develop a listing of the districts, their
populations, and cumulative populations similar to the PPS selection

76
ANNEX 4. METHODOLOGY FOR SELECTION OF SURVEY SITES BY PPS SAMPLING

described earlier. Next, determine the number of schools to survey,


based on the cumulative population using PPS.
For districts with one or more clusters to be selected, select schools
in each district using a random number table. For example, if a district
has 200 schools, number them from 1 to 200. Then, randomly select a
number from 1 to 200 using the table. If two schools are to be select-
ed, then randomly select two numbers. Finally, and while not techni-
cally correct, it would be acceptable to analyse the school-based data as
though the schools were selected using PPS methodology.

Selecting students within each selected school


Once the school has been selected, it is usual to select one class or grade,
and to sample all students in that class – both male and female. If the
schools are large, it may be necessary to divide the class, and pick one of
the divisions randomly, sampling all children in the selected portion. If
schools are small, it may be necessary to include more than one class.

Other possibilities
In situations where male and female children attend the same school, the
selection of schools and pupils would be the same as discussed above.
In situations where males and females attend separate schools, when a
school of one sex is selected the nearest school of the opposite sex should
also be surveyed.
For example, a survey is to be performed in an area where males and
females attend separate schools. Thirty schools are to be selected, and 20
pupils sampled in each. When an all-male school is visited, information
should be collected on 10 male pupils. Then, the nearest female school is
visited, and information collected on 10 female pupils.

77
ANNEX 5

Summarizing urinary iodine data:


a worked example

Some actual urinary iodine data from schoolchildren in Cameroon,


following the implementation of USI, are presented in the fi rst (left) col-
umn of Table 14. The data have been entered into a spreadsheet on a
personal computer for ease of calculation. However, with small numbers
such as these, the calculations are relatively easily performed by hand.

A5.1 Steps in processing the data


1. Before proceeding, carefully check the data entered against the origi-
nal. Ensure that the same number of data points (n) is present, and
look for any anomalous results.
2. Next, sort the data from highest to lowest, or vice-versa. The spread-
sheet will do this automatically.1 The sorted data are shown under
“Value” in Table 14, starting with the highest value, and a summary
is shown in Table 15. The next columns show the rank and percentile
for each data point.
3. The median is the middle value of the ranked data. In other words,
it is the value of the (n+1) / 2th value. In this case, there are 98 data
points, so the median is the value of (98+1) divided by 2 = 49.5th data
point. Accordingly, use the middle point between the 49th and 50th
values: 122 and 121 µg/l, respectively. The mid-point is 121.5 µg/l, so
the median is 121.5 µg/l.
4. Next, calculate the number of values below 100, 50, and 20 µg/l,
respectively. The ranking will allow this to be done very easily. In
this case, there are 33 values below 100 µg/l, 6 below 50 µg/l, and one
below 20 µg/l. These should be calculated as percentages: 33 of 98 is
33.7%, 5 of 98 is 5.1% and 1 of 98 is 1.0%.
5. Check if any values are above 500 µg/l. There is one (1.0%).
6. The 20th and 80th percentiles may be readily observed, or automati-
cally displayed using the PERCENTILE function [=PERCENTILE

1
In Microsoft Excel, use the Data Analysis function on the Tools menu, and select
“Rank and Percentile”.

78
ANNEX 5. SUMMARIZING URINARY IODINE DATA: A WORKED EXAMPLE

(range of cells, 0.2)]. The 20th percentile (P20) is 82.4 µg/l and P80
is 191.8 µg/l.
7. The “Descriptive Statistics” function of Data Analysis in Excel pro-
vides all statistics shown: select “Summary Statistics” in the dialogue
box. Note that the mean is much higher than the median, indicating
that the distribution is heavily skewed to the right. This is also shown
by the much greater distance between P80 and the median, compared
to that between P20 and the median.
8. In addition, the data can be shown as a histogram using the “Histo-
gram” function of Data Analysis in Excel. Convenient ranges need
to be chosen for making the frequency distribution, which will be
reflected in the height of each bar of the histogram. 50 µg/l is sug-
gested (i.e., the fi rst bar is 0–49 µg/l, the second 50–99 µg/l, the third
100–149 µg/l, etc.). Appropriate modifications can be made using
“Chart Options” and related functions. The histogram is shown in
Figure 6. A fully detailed description for constructing that histogram
is not given here.
In presenting this distribution, it is important not to misinterpret the
different percentages. A common mistake is to assume that there is defi-
ciency because 33.7% have a UI value <100 µg/l. This is not the correct
interpretation of the median value and distribution statistics. Instead,
this calculation shows the distribution of values around the median val-
ue, and helps determine if there is a large proportion with either very low
or very high values.
These results indicate that there is no iodine deficiency, and that salt
iodization is therefore having the required impact. There is no evidence
of significant over-iodization. No changes are needed on the basis of
these results, but further follow-up is always essential.

79
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Table 14 Urinary iodine data in Cameroon schoolchildren following


salt iodization
UI(µg/l) VALUE RANK PERCENT DESCRIPTIVE STATISTICS

141 535 1 100.00%


138 480 2 98.90% Mean 142.7449
138 395 3 97.90% Standard error 8.877338
154 340 4 96.90% Median 121.5
162 320 5 95.80% Mode 138
26 295 6 94.80% Standard deviation 87.88117
63 273 7 92.70% Sample variance 7723.099
111 273 7 92.70% Kurtosis 5.463542
120 264 9 91.70% Skewness 1.970291
65 261 10 90.70% Range 525
190 240 11 89.60% Minimum 10
142 232 12 87.60% Maximum 535
138 232 12 87.60% Sum 13989
95 224 14 86.50% Count 98
273 208 15 85.50% Confidence level (95.0%) 17.61905
132 200 16 83.50%
164 200 16 83.50%
66 198 18 82.40%
158 193 19 80.40%
114 193 19 80.40%
118 190 21 79.30%
232 188 22 78.30%
145 180 23 77.30%
94 174 24 76.20%
90 164 25 75.20%
122 162 26 74.20%
114 160 27 73.10%
340 158 28 72.10%
193 154 29 71.10%
135 150 30 70.10%
261 146 31 68.00%
75 146 31 68.00%
63 145 33 67.00%
264 144 34 65.90%
142 142 35 63.90%
174 142 35 63.90%
121 141 37 62.80%
395 140 38 60.80%
320 140 38 60.80%
240 138 40 57.70%
140 138 40 57.70%
66 138 40 57.70%
146 135 43 56.70%
115 133 44 55.60%
82 132 45 54.60%
82 128 46 53.60%
535 124 47 52.50%
74 122 48 50.50%
35 122 48 50.50% The median lies halfway between
83 121 50 49.40% these two values

80
ANNEX 5. SUMMARIZING URINARY IODINE DATA: A WORKED EXAMPLE

Table 14 continued
UI(µg/l) VALUE RANK PERCENT DESCRIPTIVE STATISTICS

104 120 51 46.30%


64 120 51 46.30%
208 120 51 46.30%
49 118 54 45.30%
89 117 55 44.30%
109 115 56 42.20%
106 115 56 42.20%
32 114 58 40.20%
128 114 58 40.20%
232 111 60 39.10%
88 110 61 38.10%
115 109 62 37.10%
144 108 63 36.00%
86 106 64 35.00%
150 104 65 34.00%
224 96 66 32.90% <100 µg/l
92 95 67 30.90%
180 95 67 30.90%
193 94 69 29.80%
133 92 70 28.80%
80 90 71 26.80%
87 90 71 26.80%
96 89 73 25.70%
120 88 74 24.70%
146 87 75 22.60%
160 87 75 22.60%
124 86 77 21.60%
90 83 78 20.60%
10 82 79 18.50%
55 82 79 18.50%
108 80 81 16.40%
480 80 81 16.40%
80 75 83 15.40%
122 74 84 14.40%
198 66 85 12.30%
200 66 85 12.30%
87 65 87 11.30%
200 64 88 10.30%
188 63 89 8.20%
54 63 89 8.20%
273 55 91 7.20%
120 54 92 6.10%
140 49 93 5.10% <50 µg/l
110 42 94 4.10%
42 35 95 3.00%
95 32 96 2.00%
117 26 97 1.00%
295 10 98 .00% <20 µg/l

81
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Table 15 Summary of results


Number 98
Median 121.5 µg/l
20th percentile 82.4 µg/l
80th percentile 191.8 µg/l
Distribution
<100 µg/l 33.7%
<50 µg/l 5.1%
<20 µg/l 1.0%
>500 µg/ 1.0%

Figure 6 Frequency table and histogram to show distribution of urinary iodine


values after iodization in Cameroon
URINARY IODINE (µg/l) FREQUENCY

0–49 6
50–99 27
100–149 35
150–199 13
200–249 7
250–299 5
300–349 2
350–399 1
400–449 0
450–499 1
500–549 1
550–599 0

40

30
# of samples

20

10

0
0–49 50–99 100– 150– 200– 250– 300– 350– 400– 450– 500– 550–
149 199 249 299 349 399 449 499 549 599
urinary iodine (µg/l)

82
ANNEX 6

Guidelines to assess
IDD national programmes1

A6.1 Background
The iodine deficiency elimination goal was set at the World Summit for
Children in 1990, and subsequently in 1993 when WHO and UNICEF
agreed to recommend USI to each nation where IDD is a public health
problem. The IDD elimination goal was reaffi rmed by multi-sec-
tor and national delegations during the UN Special Session for Chil-
dren (UNGASS) in New York, May 2002, and a timetable was set for
global elimination by 2005. At the same time, the Network for Sustained
Elimination of Iodine Deficiency (the Network) was launched at a
side event during UNGASS by the Director General of WHO which
included contributions of high-level global leaders.
Many countries are now seeking acknowledgement of their USI
accomplishments and asking for external reviews to assist them in achiev-
ing USI. The Network will provide USI/IDD review through simplified
guidelines and in a cost-effective manner. Countries that have achieved
USI can request a desk assessment by providing relevant data and infor-
mation (see Annex 1) to the Network. For countries whose progress is
stalled and with substantial gains towards USI yet to be made, external
review missions might still be needed.

A6.2 Objectives
The following guidelines provide a framework for conducting the USI/
IDD country assessment. The main objectives of the review are:
• To help governments and program managers assess and verify the
country achievement towards their goals to sustain elimination of
iodine deficiency;
• To identify lessons learned and best practices of the country pro-
grams;
• To facilitate progress comparisons across regions by means of stand-
ardized tools/guidelines;
1
Adapted from: Country review guidelines. Network for sustained elimination of iodine
deficiency. New York, 2006 (41).

83
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

• To identify ways to address bottlenecks to ensure USI;


• To recommend steps to sustain USI.

A6.3 Proposed mechanism


The process needs to be initiated by the government requesting an
external USI review/assessment through the UNICEF or WHO country
office. This step is important as it indicates national ownership and com-
mitment to the process.
Once the request is received by the UNICEF/WHO country office,
they would facilitate the preparation of country report as outlined in
Annex 1. The report should be jointly prepared with all USI/IDD part-
ners (National Coalition) in the country.
The Network Secretary will communicate with the Board members
(UNICEF, WHO, WFP, Kiwanis International, Salt Institute, EuSalt,
China National Salt Industry, ICCIDD, Micronutrient Initiative, Emory
University, US CDC, and GAIN), obtain their inputs, and involve them
as appropriate.

A6.3.1 Desk Review


Proposed criteria:
• The country report indicates that USI has been achieved as per:
— The iodine status of the population and proportion of households
with access to adequately iodized salt;
— The WHO/UNICEF/ICCIDD programmatic indicators.
• There is a need for strategic guidance and sufficient information is
available for a desk review.

Country report:
• The country report will be an important means of communicating the
country situation. It should include a short executive summary and
clear, concise summary on how the country plans to sustain the USI
achievements.
• It will be important to have the report (or at least the executive sum-
mary and country plans) available to distribute at the ‘stakeholder’/
partners consultation prior to submission to the Network.
• Please see Annex 1 for a suggested outline for the country report.
Representatives of Network member organizations could be involved in
the desk review, and if needed and resources are available, the Network
might have an external expert.

84
ANNEX 6. GUIDELINES TO ASSESS IDD NATIONAL PROGRAMMES

Figure 7 Flow chart for Network Country Review

A request from government to the UNICEF or WHO Rep in the Country.


The Country Office will inform the Regional Office and Network Secretarya on the request.

A report will be prepared by the National Coalition in coordination with government and
assistance from UNICEF, WHO and other Network member organizationsb in the country.

Network member organizationsb in the country and a local peer reviewer confirm/verify the
report/data and decision is made to organize either desk review or in country assessment.

In-country
assessment Desk review
Reports submitted to the Reports submitted to the
Secretary and the country requests Secretary and the country requests
for an in-country assessment. for a desk review.

The Secretary will share the reports Secretary will coordinate with
with Network Board members. Board members to draw on expertise
available within Network member
organizations (2–3 persons) and
If the Board agrees and resources or an external expert if needed and
are available, the Secretary will resources are available; and form a
coordinate with Board members, the virtual team for evaluation.
country and regional counterparts
for developing TORs and program
for the review mission. If resources Team reviews the report and
are available and needed, external submits recommendations to the
experts may be recruited. Network Secretary within
2 weeks.

The Country Assessment


will follow guidelines of Iodized Salt
Program Assessment Tool 3.c

Team should submit report


and recommendations to the
Network Secretary within 2 weeks
after the mission.

The Network Chair on behalf of the


Board sends the report to UNICEF/WHO
Country Representative.

UNICEF/WHO country Reps present the


final report to the government.

a
Network Secretary can be contacted at Info@iodinenetwork.net.
b
Network member organizations in the country include UNICEF, WHO, WFP, Kiwanis International, Salt Institute,
EuSalt, China National Salt Industry Corporation, ICCIDD, MI, Emory U, US CDC, and GAIN.
c
UNICEF, PAMM, MI, ICCIDD and WHO. 1995. Assessing Country Progress in Universal Salt Iodization Programs:
Iodized Salt Program Assessment Tool (ISPAT). The Micronutrient Initiative, Ottawa, Canada.

85
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

A6.3.2 External Review Mission


Proposed criteria for conducting an external review:
• National progress has been stalled;
• Early and significant gains towards USI can be predicted and alterna-
tive or different strategies are considered worthwhile;
• Evidence of senior political commitment to goal achievement and
national commitment to success is apparent;
• There is a need for an external mission.

Assessment team composition:


• Senior officers from selected central ministries and governmental
departments;
• National coalition/committee;
• Salt producers, technicians, and traders;
• Civil, scientific, and communications elements of society;
• Representatives from the border inspection systems, importers and
exporters, law enforcement personnel, agriculture and education;
• Senior officers from resident development agencies in the country,
and representatives of other network member organizations, where
possible;
• One or two regional/international consultants.
Country assessment and mission report will follow the procedure and
format suggested in ISPAT (1999).

A6.3.3 Proposed outline for reporting country USI achievement


The country report should include:
• Executive summary: A summary of country USI/IDD status,
analyses, and recommendations.
• Summary of country action plans: Key action plans for strength-
ening and sustaining the achievements.
• Country profi le: In this section, a brief summary of information on
the country is collected and recorded. It should provide a summary
of the geographical and administrative description of the country,
including demographics, vital health statistics, and basic government
organization. A description of the health care system in the coun-
try should be provided, including an estimated health budget, and
the budget for iodine deficiency elimination program activities –
including the budget for the USI component. It would be useful to
plot an historic time-line marking significant program activities for
the past 10 to 20 years.

86
ANNEX 6. GUIDELINES TO ASSESS IDD NATIONAL PROGRAMMES

Country assessment
a. The product
This section should include information on all aspects of salt production
or imports. It should focus on those aspects that pertain to the entire salt
industry and should provide details on those areas of industry responsi-
bility that can be improved and sustained. The discussion includes:
• Achievement of change in practices by food processing industries;
• Analysis of relationships between regulatory authorities and practices
and salt producers and practices;
• Analysis of utility and impact of product advertising on public
demand, use and understanding;
• Analysis of quality assurance at iodized salt production;
• Analysis on data of salt importation, production and iodization pro-
cess, distribution, major companies, small scale producers/salt farm-
ers, association of salt producers, prices of products and the market
situation;
• Analysis on availability and procurement of KIO3 ;
• A summary of salt situation (see Table 16);
• A summary of lessons learned;
• Key action plans related to the product might be elaborated.

Table 16 Summary of salt situation


SALT IODIZED NOT IODIZED TOTAL

Total produced/imported Total


(total salt available in country) Local Production
Import
Industrial (non-food grade) Total
Food grade (including animal salt) Total

b. The process
This section should include all elements necessary for the long-term con-
tinuation of the program. The focus should be on elements that are the
roles and responsibility of the national IDD program, or of other branch-
es of the government. This should include assessments of each element’s
strengths and weaknesses, with specific suggestions for improvement.
The discussion includes:
• Analysis of the political process and how that has been nurtured and
sustained, and with what measurable results;
• Analysis of the history of formation of a National Coalition to assure
achievement of USI and Sustained Iodine Nutrition and the current
practices and issues;

87
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

• Analysis on laws and regulations, inspection, and enforcement proc-


esses in the country for USI and some indication of practice and
results;
• Analysis of government oversight practices and procedures;
• Achievement of penetration into learning systems;
• Achievement of insertion of essential knowledge on iodine nutrition in
the training of medical practitioners and other health personnel;
• Achievement of insertion in animal husbandry and some indication of
impact and increase of iodized salt use for animals;
• Analysis of the communications tactics and strategies and the poten-
tial of their permanency;
• Analysis of national management capacities including appointment of
a responsible officer for IDD elimination program;
• Analysis of fi nancial commitments of state authorities, central budg-
ets, and expenditure patterns, including private sector and civic sec-
tor commitments; and degree to which the nation is positioned with
national resources to sustain iodine nutrition forever;
• Analysis of impact of international aid and collaboration;
• Analysis of potential for success absent international aid;
• A summary of lessons learned;
• Key action plans related to the process.

c. Households access to iodized salt and iodine nutrition status


This section should provide a summary of the most current data in the
last two years on household and retail iodized salt coverage/access, and
on the iodine nutrition status (urinary iodine concentration: median,
percentage of population below 20 µg/l) of a population. If an independ-
ent, population-based survey (preferably nationally representative) is
included, data methods should be described, and a summary presented.
The discussion should include data collection methods and an assess-
ment of the coverage and prevalence figures presented. The discussion
includes:
• Achievement of government practices and procedures for obtaining,
analyzing, publishing and utilizing data and information.
• Analysis of commitments to assess and reassess the progress towards
elimination with access to laboratories able to provide accurate data
on salt and urinary iodine. This should include:
— Regular data on salt iodine at the factory, retail, and household
levels, and regular laboratory data on UIE in school-age children
with appropriate sampling for higher risk areas;
— A database for recording of results of regular monitoring proce-

88
ANNEX 6. GUIDELINES TO ASSESS IDD NATIONAL PROGRAMMES

dures particularly for salt iodine, UIE, and if available neonatal


TSH monitoring with mandatory public reporting.
• Analysis on trends/changes in iodized salt coverage and iodine status
over time (last 10 years if possible).
• Achievement of public health laboratories related to iodine nutrition,
their management, quality control practices and procedures.
• Program infrastructure, oversight committee, staff, budget, type and
number of laboratories and annual number of samples processed.
• A summary of lessons learned.
• Key action plans to sustain regular USI monitoring and evaluation.

d. A summary of Country Program assessments by WHO, UNICEF, and IC CIDD

Table 17 Summary of Country Program assessments


PROGRAMMATIC COUNTRY PROGRAM ACTION PLANS TO
INDICATORS SITUATIONS SUSTAIN USI

1. Presence of a national multi-sector


coalition responsible to the government
for the national programme for the
elimination of IDD with the following
characteristics:
– National stature;
– All concerned sectors, including the
salt industry, represented, with
defined roles and responsibilities;
– Convenes at least twice yearly.
2. Demonstration of political commitment
as reflected by:
– Inclusion of IDD in the national
budget (either as specific programme
funds or through inclusion in existing
programme funds) particularly with
regard to procurement and
distribution of KI03.
3. Enactment of legislation and supportive
regulations on universal salt iodization,
which establishes a routine mechanism
for external quality assurance.
4. Establishment of methods for assess-
ment of progress in the elimination of
IDD as reflected by:
– Reporting on national programme
progress every three years.

89
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Table 17 Continued
PROGRAMMATIC COUNTRY PROGRAM ACTION PLANS TO
INDICATORS SITUATIONS SUSTAIN USI

5. Access to laboratories as defined by:


– Laboratories able to provide accurate
data on salt and urinary iodine levels
and thyroid function.
6. Establishment of a programme of
education and social mobilization as
defined by:
– Inclusion of information on the
importance of iodine and the use of
iodized salt, within educational
curricula.
7. Routine availability of data on salt
iodine content as defined by:
– Availability at the factory level at
least monthly, and at the household
level at least every five years.
8. Routine availability of population-based
data on urinary iodine every five years.
9. Demonstration of ongoing cooperation
from the salt industry as reflected by:
– Maintenance of quality control
measures and absorption of the cost
of iodate/iodide.
10. Presence of a national database for
recording of results of regular
monitoring procedures which include
population-based household coverage
and urinary iodine (with other indicators
of iodine status and thyroid function
included as available).

Conclusions
Conclusion on the country situation analysis and summary of agreed key
action plans to sustain ID elimination in the country.

90
ANNEX 7

List of Contributors

Bruno de Benoist
Micronutrient Malnutrition Unit (MNM)
Department of Nutrition for Health and Development
World Health Organization
20 Avenue Appia
CH-1211, Geneva 27
Switzerland
Tel: +41 22 791 3412
Fax: +41 22 791 4156
E-mail: debenoistb@who.int

Gerard N. Burrow
Chairman
International Council for Control of Iodine Deficiency Disorders
110 Deepwood Drive
Hamden, CT 06517
USA
E-mail: gburrow55@comcast.net

François Delange1
ICCIDD
Hyde Park Residence
Chaussée de Waterloo 965 D.O.3
B 1180 Brussels
Belgium
Tel: +32 (2) 660 04 08
Fax: +32 (2) 660 0408
E-mail: fdelange@ulb.ac.be

1
Deceased

91
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Jonathan Gorstein
University of Washington
School of Public Health and Community Medicine
H-688 Health Sciences Building
Box 357660
1959 NE Pacific St.
Seattle, WA 98195
United States of America
Tel: 206–616–8530
Fax: 206–543–3964
Email: gorstein@u.washington.edu

Robin Houston
Monitoring and evaluation for vitamin A
MOST Project
9455 Big Gulch Road
Bozeman, MT 59715
United States of America
Tel: +1 (406) 582 7959
Fax: +1 (406) 582 7959
E-mail: houstonrmh@yahoo.com

Pieter Jooste
Nutritional Intervention Research Unit
PO Box 19070
Tygerberg 7505
Cape Town
South Africa
Tel: +27 (0) 21 938-0370
Fax: +27 (0) 21 938-0321
E-mail: pieter.jooste@mrc.ac.za

Nuné Mangasaryan
Nutrition and Child Growth & Development
Programme Division
United Nations Children’s Fund (UNICEF)
3 United Nations Plaza, New York
NY 10017, USA
Tel: + 1 212 326 71 59
Fax: + 1 212 326 71 29
E-mail: nmangasaryan@unicef.org

92
ANNEX 7. LIST OF CONTRIBUTORS

Erin McLean
Micronutrient Malnutrition Unit (MNM)
Department of Nutrition for Health and Development
World Health Organization
20 Avenue Appia
CH-1211, Geneva 27
Switzerland
Tel: +41 22 791 3348
Fax: +41 22 791 4156
E-mail: mcleane@who.int

Eduardo Pretell
ICCIDD
Av. Paseo de la República 3691, Of. 401-A
San Isidro, Lima 27, Perú
E-mail: epretell@terra.com.pe
Tel: +(51-1) 421-0882
Fax: +(51-1) 421-3065
E-mail: epretell@terra.com.pe

Lisa Rogers
Micronutrient Malnutrition Unit (MNM)
Department of Nutrition for Health and Development
World Health Organization
20 Avenue Appia
CH-1211, Geneva 27
Switzerland
Tel: +41 22 791 1957
Fax: +41 22 791 4156
E-mail: rogersl@who.int

Kevin Sullivan
Department of Pediatrics, Epidemiology and International Health
Emory University
1518 Clifton Road, N.E.
Atlanta, GA 30322
United States of America
Tel.: +1 (404) 727 8714
Fax: +1 (404) 727 5369
E-mail: cdckms@sph.emory.edu

93
ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION

Juliawati Untoro
Nutrition and Child Growth & Development
Programme Division
United Nations Children’s Fund (UNICEF)
3 United Nations Plaza, New York
NY 10017, USA
Tel: + 1 212 326 73 68
Fax: + 1 212 326 71 29
E-mail: juntoro@unicef.org

Michael Zimmermann
Laboratory of Human Nutrition
Swiss Federal Institute of Technology (ETH) Zürich
ETH Zentrum, Schmelzbergstrasse 7, LFV E19
CH-8092 Zürich
Switzerland
Tel: +41 44 632 8657
Fax: +41 44 632 1470
E-mail: michael.zimmermann@ilw.agrl.ethz.ch

94
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ASSESSMENT OF IODINE DEFICIENCY DISORDERS AND MONITORING THEIR ELIMINATION
Assessment of
iodine deficiency disorders and
monitoring their elimination
This document is intended primarily for managers of national program-
mes for the prevention and control of micronutrient malnutrition.
It sets out principles governing the use of surveillance indicators in imple-
menting interventions to prevent, control, and monitor iodine deficiency
disorders (IDD). It presents methods for monitoring iodine status and
determining urinary iodine and provides guidelines on the procedures for
monitoring salt iodine content, whether at the factory, importation site, or
household level. It also gives guidance on conducting surveys to assess
iodine status in populations.
Finally, indicators are presented for monitoring progress towards achie-
ving the goal of sustainable elimination of IDD as a significant public
health problem.

A GUIDE FOR PROGRAMME MANAGERS


Third edition

ISBN 978 92 4 159582 7


WHO

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